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United States Patent (19) 11 Patent Number: 6,143,514 Ullman Et Al

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United States Patent (19) 11 Patent Number: 6,143,514 Ullman Et Al USOO6143514A United States Patent (19) 11 Patent Number: 6,143,514 Ullman et al. (45) Date of Patent: *Nov. 7, 2000 54 CHEMILUMINESCENT COMPOSITIONS McCapra, et al., Luminescent Labels for AND THEIR USE IN THE DETECTION OF Immunoassay-From Concept to Practice; Journal of Biolu HYDROGEN PEROXDE minescence and Chemiluminescence; 4:51-58; 1989. Seitz, Rudolf W.; Immunoassay Labels Based on Chemilu 75 Inventors: Edwin F. Ullman, Atherton; Sharat minescence and Bioluminescence; Clin. Biochemistry; Singh, San Jose, both of Calif. 17:120-125; 1984. 73 Assignee: Dade Behring Marburg GmbH, Seliger, et al.; Chemiluminescence of Benzoa Pyrene-7, Marburg, Germany 8-Diol; Photochem. Photobiol.; 36:359-365; 1982. Lee, et al., Chemiluminescence from the Reaction of Singlet * Notice: This patent issued on a continued pros Oxygen with 10,10'-Dimethyl-9,9'-biacridylidene. A Reac ecution application filed under 37 CFR tive 1,2-Dioxetane; J. Org. Chem.; 41 No. 16:2685–2688; 1.53(d), and is subject to the twenty year 1976. patent term provisions of 35 U.S.C. Grayeski, Mary Lynn; Chemi- and Bioluminescence, edited 154(a)(2). by John G. Burr, Marcel Dekker, Inc.; 16:469-493; 1985. McCapra, F., Potential applications of bioluminescence and 21 Appl. No.: 08/850,026 chemiluminescence in biosensors, BioSensors Fundamentals 22 Filed: May 1, 1997 and Applications; No. 31:617-637; 1987. McCapra, F. et al.; Selected Chemical Reactions That Pro Related U.S. Application Data duce Light, Bioluminescence and Chemiluminescence; 60 Provisional application No. 60/017,075, May 1, 1996. Instruments and Applications, 1:9-42. Poulsen, J.R., et al.; Solid-State Peroxyoxalate Chemilumi 51 Int. Cl." ................................ C12O 1/28; C12O 1/54 nescence Detection of Hydrogen Peroxide Generated in a 52 U.S. Cl. ................................... 435/28; 435/6; 435/14; Post-Column Reaction; J. Chromatography; 360 No. 435/177; 435/180 2:371-383; Jun. 25, 1986. 58 Field of Search ..................................... 435/177, 180, Wasserman, H.; et al.; Singlet Oxygen; Academic Press; No. 435/7.5, 7.9, 28, 14, 192, 6; 436/534, 528 12:597–641; 1979. 56) References Cited E. Ullman et al., Clinical Chemistry, vol. 42, No. 9, pp. 1518-1526, 1996. U.S. PATENT DOCUMENTS 4,233,402 11/1980 Maggio et al. Primary Examiner Mary E. Ceperley 5,084,381 1/1992 Akimoto et al.. Attorney, Agent, or Firm Patrick G. Gattari 5,332,662 7/1994 Ullman. 5.532,138 7/1996 Singh et al.. 57 ABSTRACT 5,536,834 7/1996 Singh et al. .............................. 544/98 5,556,758 9/1996 Allen. Compositions, methods and kits are disclosed. The compo 5,578.498 11/1996 Singh et al. ............................ 436/518 Sitions comprise a matrix having incorporated therein a label 5,616,719 4/1997 Davalian et al. ... 546/334 capable of being modified by Singlet oxygen. A catalyst 5,618,732 4/1997 Pease et al. ...... ... 436/8 capable of catalyzing the formation of Singlet oxygen is 5,709,994 1/1998 Pease et al. ................................. 435/4 bound to the matrix, which permits the diffusion of singlet oxygen therein. The compositions may be used in methods OTHER PUBLICATIONS for detecting hydrogen peroxide or a compound capable of O'Connell, et al.; A Highly Sensitive Immunoassay System generating hydrogen peroxide. A Sample Suspected of con Involving Antibody-Coated Tubes and Liposome-En taining Such compound is combined with a composition in trapped Dye; Clin. Chem.; 31/9: 1424–1426; 1985. accordance with the present invention. The combination is Ullman, et al., Luminescent oxygen channeling assay Subjected to conditions wherein Such compound generates (LOCITM): sensitive, broadly applicable homogeneous hydrogen peroxide. The reaction of Singlet oxygen with the immunoassay method; Clin. Chem.; 42/9:1518-1526, 1996. label is determined, the reaction thereof indicating the Ullman, et al., Luminescent oxygen channeling immunoas presence of the compound capable of generating hydrogen Say: Measurement of particle binding kinetics by chemilu peroxide. minescence; Proc. Natl. Acad. Sci. USA; 91:5426–5430; 1994. 47 Claims, No Drawings 6,143,514 1 2 CHEMILUMNESCENT COMPOSITIONS reason, luminescers have been utilized as labels in assays AND THEIR USE IN THE DETECTION OF Such as nucleic acid assays and immunoassayS. For example, HYDROGEN PEROXDE a member of a specific binding pair is conjugated to a lumineScer and various protocols are employed. The lumi This application claims the benefit of U.S. Provisional neScer conjugate can be partitioned between a Solid phase Application No. 60/017,075 filed May 1, 1996. and a liquid phase in relation to the amount of analyte in a Sample Suspected of containing the analyte. By measuring BACKGROUND OF THE INVENTION the luminescence of either of the phases, one can relate the level of luminescence observed to a concentration of the 1. Field of the Invention analyte in the Sample. This invention relates to methods, compositions and kits Particles, Such as liposomes and erythrocyte ghosts, have for detecting hydrogen peroxide or a compound capable of been utilized as carriers of encapsulated water Soluble generating hydrogen peroxide. materials. For example, liposomes have been employed to The clinical diagnostic field has seen a broad expansion in encapsulate biologically active material for a variety of uses, recent years, both as to the variety of materials of interest 15 Such as drug delivery Systems wherein a medicament is that may be readily and accurately determined, as well as the entrapped during lipoSome preparation and then adminis methods for the determination. Convenient, reliable and tered to the patient to be treated. non-hazardous means for detecting the presence of low Particles, Such as lateX beads and liposomes, have also concentrations of materials in liquids is desired. In clinical been utilized in assayS. For example, in homogeneous assays chemistry these materials may be present in body fluids in an enzyme may be entrapped in the aqueous phase of a concentrations below 10° molar. The difficulty of detect liposome labeled with an antibody or antigen. The liposomes ing low concentrations of these materials is enhanced by the are caused to release the enzyme in the presence of a Sample relatively Small Sample sizes that can be utilized. and complement. Antibody or antigen-labeled liposomes, Detection of low concentrations of hydrogen peroxide is having water Soluble fluorescent or non-fluorescent dyes useful for numerous analytical procedures, particularly in 25 encapsulated within an aqueous phase vesicle or lipid clinical chemistry. Hydrogen peroxide is produced by cells soluble dyes dissolved in the lipid bilayer of a lipid, have Such as monocytes and is an indicator of monocyte activa also been utilized to assay for analytes capable of entering tion. Additionally, any material of interest that is or can be into an immunochemical reaction with the Surface bound converted to a Substrate for an oxidase Such as Xanthene antibody or antigen. Detergents have been used to release oxidase, amino acid oxidase, NADH oxidase, glucose the dyes from the aqueous phase of the liposomes. oxidase, galactose oxidase, glycerol phosphate oxidase, and 2. Brief Description of the Related Art the like can be detected by the hydrogen peroxide that is U.S. Pat. No. 5,084,381 (Akimoto, et al.) discusses an produced by the action of the enzyme on the Substrate. Tests assay method for detecting hydrogen peroxide. for glucose, triglycerides, d-amino acids, and cholesterol can be routinely carried out by detecting hydrogen peroxide, 35 Processes and materials for carrying out Specific binding usually by reaction of a peroxidase and a chromogenic assays is disclosed in patent application WO 86/01899 Substrate. Enzyme immunoassays using an oxidase Such as (Davis, et al.). glucose oxidase as a label also depend on a Sensitive U.S. Pat. No. 5,108,893 (Baret) discloses the use of detection method for hydrogen peroxide. For example, when oxidase enzyme Systems in chemiluminescent assayS. glucose oxidase is used as a label, the hydrogen peroxide can 40 European Patent Application 0 421 788 A2 (Allen) dis be detected using horseradish peroxidase and a chromogenic closes a haloperoxidase-acid-Oxidant chemiluminescence Substrate, or the hydrogen peroxide can be detected electro assay System for determining the presence or amount of an chemically. analyte in a liquid Sample. Detection of hydrogen peroxide is also becoming more U.S. Pat. No. 4,315,998 discusses polymer-bound photo important in the area of foodstuffs. For example, in Some 45 Sensitizing catalysts. countries hydrogen peroxide is used as a bleaching agent for Photoactivatable chemiluminescent matrices are food. It is important that residual levels of hydrogen perOX described in patent application WO94/03812 (Pease, et al.). ide in the food after bleaching be substantially zero to avoid European Patent Application No. 0515 194 A2 discloses health hazards. assay methods utilizing induced luminescence. The refer A method that has higher Sensitivity, leSS interference 50 ences cited therein are incorporated herein by reference from the Sample, and uses fewer, and more stable, reagents including without limitation U.S. Pat. No. 5,017,473 would increase the Simplicity and reliability of assays for, or (Wagner), which discloses a homogeneous chemilumines depending on, hydrogen peroxide detection. cence immunoassay using a light absorbing material, Euro pean Patent Application No. 0,345,776 (McCapra), which Homogeneous immunoassays have previously been 55 discloses Specific binding assays that utilize a Sensitizer as a described for Small molecules. These assays include Syva label, U.S. Pat. No. 4,193,983 (Ullman, et al.), which Company’s FRATOR assay, EMITOR assay, enzyme channel discloses labeled liposome particle compositions and immu ing immunoassay, and fluorescence energy transfer immu noassays therewith, U.S. Pat. No. 4,891,324 (Pease, et al.), noassay (FETI); enzyme inhibitor immunoassays (Hoffman which describes a particle with lumineScer for assayS.
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