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WO2008147345A2 - Système et procédé pour la détection indépendante de la structure d'antigène d'antigènes capturés sur des matrices d'anticorps - Google Patents

Système et procédé pour la détection indépendante de la structure d'antigène d'antigènes capturés sur des matrices d'anticorps Download PDF

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WO2008147345A2
WO2008147345A2 PCT/US2005/019939 US2005019939W WO2008147345A2 WO 2008147345 A2 WO2008147345 A2 WO 2008147345A2 US 2005019939 W US2005019939 W US 2005019939W WO 2008147345 A2 WO2008147345 A2 WO 2008147345A2
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antibodies
antibody array
antibody
antigen
antigens
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WO2008147345A3 (fr
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George Dacai Liu
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    • 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
    • G01N33/6803—General methods of protein analysis not limited to specific proteins or families of proteins
    • G01N33/6845—Methods of identifying protein-protein interactions in protein mixtures
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • 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

  • the present invention generally relates to antibody arrays, and more particularly to systems and methods for antigen structure-independent detection of antigens captured on antibody arrays.
  • a protein-detecting microarray comprises many different affinity reagents (frequently antibodies) arrayed at high spatial density on a solid support. Each agent captures its target protein from a complex mixture (such as serum or cell lysate), and the captured proteins are subsequently detected and quantified.
  • the protein microarray format enables fast, easy and parallel detection of thousands of addressable proteins and side-by-side measurements. It may be applied to analyze antibody-antigen, protein- protein, protein-nucleic acid, protein-lipid and protein-small-molecule interactions, as well as enzyme-substrate interactions.
  • the captured proteins in an antibody array are detected in two ways.
  • One is a sandwich immunoassay in which capture antibodies are immobilized on the solid support, and the bound proteins are detected using a second, labeled detection antibody.
  • Huang et al. (Anal. Biochem. 2001, 294:55-62) described an ECL based immunoassay array for the simultaneous assay of 24 cytokines from either cultured media or patient sera. The system was based on the standard sandwich ELISA technology but the initial capture antibodies raised to the various cytokines were transferred in an ordered format onto a membrane. It is evident that this type of antibody array is a simple collection of multiple individual ELISA assays.
  • Haab et al. (Genome Biol., 2001, 2research0004.1- 0004.13) labeled two samples independently with distinguishable fluorophores and mixed the samples before applying them to the array.
  • this method does not offer signal amplification beyond that provided by the use of fluorophores.
  • the labeling is time consuming and some proteins may be labeled preferentially on their antigenic epitopes and lose their ability to be captured by their affinity reagents.
  • the present invention provides a system and method for detecting antigens captured on an antibody array.
  • the method comprises the following steps of providing the antibody array having at least two antibodies, contacting the antibody array with a sample containing at least one antigen that may be captured by the antibodies disposed on the antibody array, and detecting the at least one antigen captured by the antibody array with a detecting agent that specifically binds to the antigen-bound antibodies on the antibody array, thereby the at least one antigen captured by the antibody array can be detected independent of the structures of the antigens.
  • CIq is used as the detecting agent to detect antigen-bound antibodies.
  • one object of the present invention is to provide systems and methods for their applications in proteomics, wherein the systems and methods are highly specific and sensitive, and easily adapted to automation.
  • the present invention provides systems and methods of utilizing an antibody array for simultaneously detecting different antigens regardless of the antigen structures.
  • the practice of the present invention will employ, unless otherwise indicated, conventional techniques of molecular biology (including recombinant techniques), microbiology, cell biology, biochemistry and immunology, which are known to those skilled in the art.
  • monoclonal and polyclonal antibodies can be produced for different antigens in different hosts by known methods.
  • the manipulation of the antibodies is also known.
  • the production and preparation of antigens are also known to those skilled in the art. Thus, no citation to or detailed description of the known techniques will be given herein for the sake of brevity.
  • one molecule or one class of molecules can be induced to perform certain similar, if not identical, function(s) by the interactions (e.g., binding) with different entities, regardless of the structures of the entities interacted with the molecule(s).
  • the typical molecules are the antibodies in animals including mouse, rat, rabbit, pig, goat, horse, dog and human beings.
  • the IgGs will go conformational changes so that the first component of the classical complement pathway, CIq, can bind to the IgGs, resulting in the activation of the classical complement pathway.
  • Antibody as used herein is intended to cover any molecule or any class of molecules on which at least one shared conformational epitope can be induced by two or more different antigens. It is to be noted that the definition is function-based. While the examples illustrate the induction of new conformational epitopes recognized by CIq, it is to be appreciated that the loss of conformational epitopes on antigen-bound antibodies may also be utilized to detect and/or verify the binding of antigens.
  • An applicable antibody may include conventional antibodies, antibody mimics and receptors.
  • the conventional antibodies can encompass monoclonal, polyclonal antibodies, chimeric antibodies, single chain, and mutants thereof.
  • Antibodies may be murine, rat, rabbit, chicken, human, or any other origin (including humanized antibodies). General techniques for antibodies are known in the art.
  • Antigen refers to any entity that binds to an antibody disposed on an antibody array and induces at least one shared conformational epitope on the antibody.
  • Antigens could be proteins, peptides, antibodies, small molecules, lipid, carbohydrates, nucleic acid, and allergens.
  • An antigen may be in its pure form or in a sample in which the antigen is mixed with other components.
  • Antibody array refers to a linear or two-dimensional array of two or more different antibodies formed on the surface of a solid support.
  • Detecting agent refers to any molecule that has the ability to selectively bind to immobilized antibodies on an antibody array that have at least one shared conformational epitope resulting from the binding of antigens. The detecting agent will not bind, or bind at an insignificant level the antibodies immobilized on an antibody array if the antibodies are not bound with their correspondingly antigens.
  • the shared conformational epitopes may be new ones induced by the antigens or lost ones destroyed by the antigens.
  • the detecting agent includes proteins (e.g., CIq, RF), peptides (C Iq fragments), and antibodies that specifically recognize the shared conformational epitopes.
  • proteins e.g., CIq, RF
  • peptides C Iq fragments
  • antibodies that specifically recognize the shared conformational epitopes.
  • An antibody array is an ordered spatial arrangement of two or more antibodies on a physical substrate. Row and column arrangements are preferred due to the relative simplicity in making and assessing such arrangements.
  • the spatial arrangement can, however, be essentially any form selected by the user, and preferably but need not be, in a pattern.
  • the most common form of antibody arrays is that antibodies that bind specific antigens are arrayed on a glass slide at high density. A sample containing possible antigens is passed over the array and the bound antigen is detected after washing.
  • the antibodies in an antibody array are preferably printed onto a solid support.
  • silica or glass is most often used because of its great chemical resistance against solvents, its mechanical stability, its low intrinsic fluorescence properties, and its flexibility of being readily functionalized.
  • solid supports include polypropylene, polystyerene, polyethylene, dextran, nylon, amylases, glass, natural and modified celluloses, polyacrylamides, agaroses and magnetite. Those skilled in the art will know of other suitable solid support for binding antibodies, or will be able to ascertain such, using routine experimentation.
  • Antibodies may be immobilized onto a support surface either by chemical ligation through a covalent bond or non-covalent binding.
  • a support surface There are many known methods for covalently immobilizing antibodies onto a solid support.
  • MacBeath et al. J Am Chem Soc, 1999, 121 :7967-7968
  • Antibodies may be attached to various kinds of surface via diffusion, adsorption/absorption, covalent cross-linking and affinity. Antibodies may be directly spotted onto plain glass surface. To keep antibodies in a wet environment during the printing process, high percent glycerol (30-40%) may be used in sample buffer and the spotting is carried out in a humidity-controlled environment.
  • the surface of a substrate may be modified to achieve better binding capacity.
  • the glass surface may be coated with a thin nitrocellulose membrane or poly-L-lysine such that antibodies can be passively adsorbed to the modified surface through non-specific interactions.
  • streptavidin may be arrayed onto solid surfaces for capture of biotinylated proteins.
  • Antibody arrays can be fabricated by the transfer of antibodies onto the solid surface in an organized high-density format followed by chemical immobilization.
  • the techniques for fabrication of an array include, but are not limited to, photolithography, ink jet and contact printing, liquid dispensing and piezoelectrics.
  • the patterns and dimensions of antibody arrays are to be determined by each specific application. The sizes of each antibody spots may be easily controlled by the users.
  • the present invention takes advantage of the shared conformational epitopes on antibodies resulting from the binding of antigens.
  • the shared conformational epitopes can be induced or destroyed by different antigenic epitopes from one antigen or different antigenic epitopes from different antigens.
  • the detecting agent of the present invention is capable of recognizing at least one shared conformational epitope present in all antigen-bound antibodies in an antibody array so that the detection of antigens bound to an antibody array is independent of the structure of the antigens.
  • the nature of the detecting agent is not important for the present invention as long as the detecting agent is applicable for the present invention.
  • the present invention provides the detecting agents including complement I q (C I q) and rheumatoid factor (Rf). Both C I q and RF have the property of binding to antibodies that are part of complexes formed between antibodies and antigens, but essentially do not bind to non-complexed antibodies. Both C Iq and RF have been used to measure circulating immune complexes. See, U.S. patent 4,143,124; and PCT, WO 97/01758. C I q is the first component of the classical complement cascade pathway, which is commonly present in animals including mouse, rat, rabbit, sheep, goat, horse, cattle, dog and human beings.
  • C Iq shares high homology with similar structures from different species and has cross species activities.
  • C I q applicable in the present invention is not limited to any C I q from a specific species.
  • human C I q is a glycoprotein of about 460 kDa.
  • C Iq appears as a bunch of tulips, with six globular heads, each connected by a stalk to a central bundle of fibers.
  • One CI q molecule is composed of 18 polypeptide chains. The chains are of three different types named A, B, and C, of 29, 27, and 23 kDa, respectively. They are linked by disulfide bonds to form six A-B and three C-C dimers.
  • Each of the six individual segments of CIq comprises one chain of each type, which acquire a triple helical structure in the fibrillar region. See, e.g., Kaul and Loos, The Journal of Biological Chemistry, 1997, 272:33234-33244.
  • C Iq binds to antibodies in antigen-antibody complexes, but not free antibodies.
  • the binding of C Iq to antibodies may be optimized by exploring incubation time, incubation temperature. pH values, and ionic strengths.
  • the optimized conditions for each antibody array can be obtained with methods well known to those skilled in the art. Sec, Tan ct al., Proc. Natl. Acad. Sci. USA, 1990, 87: 162-166; Marques et al., The Journal of Biological Chemistry, 1993, 268: 10393- 10402.
  • C Iq as used herein includes any C Iq portions or fragments that retain the capacity of binding to antigen-bound antibodies. Fragments of CIq and peptides prepared synthetically are described in WO 92/07267.
  • Rheumatoid factors are antiglobulin antibodies that bind IgG immunoglobulins and are found in the serum and synovial fluid of most patients with rheumatoid arthritis. Certain RFs can bind to neoantigens created within IgG by the formation of antigen-antibody immune complexes. See, U.S. Patent 5,252,461.
  • RF is a known material and methods for its preparation and isolation is known. See, U.S. Patent 4,143, 124. A portion or fragment of RF can also be used for this invention if it retains its binding capacity. See, PCT/DK96/00288.
  • the present invention provides methods for detecting the antigens bound to the antibody array as described hereinabove. Briefly, the methods comprise the steps of providing an antibody array, contacting the array with a sample containing antigens, and detecting the bound antigens by using the detecting molecules against the antibodies. The process can be done manually and/or automatically. The handling of arrays is well known to those skilled in the art.
  • sample encompasses a variety of sample types and/or origins, such as blood and other liquid samples of biological origin, solid tissue samples such as a biopsy specimen or tissue cultures or cells derived therefrom, and the progeny thereof.
  • sample encompasses a clinical sample, and also includes cells in culture, cell supernatants, cell lysates, serum, plasma, biological fluid, and a pure or enriched bacterial or viral sample derived from any of these, for example, as when a sample is cultured in order to increase, enrich and/or substantially purify a bacterial or viral sample therefrom.
  • a sample can be from microorganisms, e.g., bacteria, yeasts, viruses, viroids, molds, fungi, plants, animals, including mammals such as humans.
  • a sample may comprise a single cell or more than a single cell.
  • These samples can be prepared by methods known in the art such as lysing, fractionation, purification, including affinity purification, FACS, laser capture microdissection or iospycnic centrigugation.
  • the antibody array is contacted with a sample, the formation of antibody:antigen complexes can be performed under a variety of conditions. It is also true for the reaction of the detecting molecules with the antibodies.
  • the reaction solutions can contain varying degrees of salt or have varying pH values.
  • the binding reaction can be carried out at varying temperature.
  • pH conditions will range from 2-10 (most preferably around pH7), temperatures from 4-45 0 C (preferably 15-3O 0 C) and salt conditions from l ⁇ m to 5M (in the case of NaCl).
  • the readout of the detecting agents bound to the antibodies in an antibody array can take up many forms.
  • the antigens in a sample and the second detecting molecules e.g., antibodies against the detecting molecules such as anti-Clq antibodies
  • the antigens in a sample can be labeled with fluorescent dyes or detected by their specific antibodies in combination with the detecting agents to quantify and/or verify the binding antigens. Therefore, the detection methods for detecting agents may be compatible with other immunoassays as users desire.
  • detectably labeled is intended to encompass antigen or detecting agent directly coupled to a detectable substance, such as a fluorescent dye, and antigen or detecting agent coupled to a member of binding pair, such as biotin/streptavidin, or an epitope tag that can specifically interact with a molecule that can be detected, such as by producing a colored substrate or fluorescence.
  • a detectable substance such as a fluorescent dye
  • antigen or detecting agent coupled to a member of binding pair, such as biotin/streptavidin, or an epitope tag that can specifically interact with a molecule that can be detected, such as by producing a colored substrate or fluorescence.
  • Fluorescence detection methods are generally the preferred detection method because they are simple, safe, extremely sensitive and can have very high resolution.
  • an antibody array is either directly probed with a fluorescent detecting molecule or in two step by first using a tagged probe (e.g., biotin), which can then be detected in a second step using a fluorescently labeled affinity reagent (e.g., streptavidin).
  • a tagged probe e.g., biotin
  • a fluorescently labeled affinity reagent e.g., streptavidin
  • a biotin labeled target can be detected by gold-conjugated streptavidin with silver enhance solution so that the resultant black image of microarray spots can be easily detected with a commercial CCD camera.
  • the detecting agents e.g., CIq and RF
  • anti-detecting agent antibodies may be attached by the 5' end of an oligonucleotide primer. Then the signals may be significantly increased by Rolling circle amplification (RCA). In the presence of a DNA circle, DNA polymerase and nucleotides, rolling circle replication generates a concatamer of circle DNA sequence copies that remain attached to the antibody. The concatamer is then detected by the hybridization of fluorescent, complementary oligonucleotide probes.
  • RCA Rolling circle amplification
  • CIq that binds to the antibody array can be detected using any means known in the art.
  • the CIq is labeled, using any methods known in the art. See, U.S. Patent 4,882,423.
  • the CIq may be labeled with one or more labeling moieties including compositions that can be detected by photochemical, spectroscopic, biochemical, immunochemical, chemical, optical, electrical, bioelectronic, etc. means.
  • useful protein labels include radiolabels (e.g., 3H, 1251, 35S, 14C, or 32P), fluorescent dyes (e.g., fluorescein isothiocyanate, Texas red, rhodamine, and the like); electron-dense reagents, enzymes (e.g., LacZ, CAT, horse radish peroxidase, alkaline phosphatase and others, commonly used as detectable enzymes, either as marker gene products or in an ELISA); biotin, dioxigenin, or haptens and proteins for which antisera or monoclonal antibodies are available.
  • radiolabels e.g., 3H, 1251, 35S, 14C, or 32P
  • fluorescent dyes e.g., fluorescein isothiocyanate, Texas red, rhodamine, and the like
  • electron-dense reagents e.g., LacZ, CAT, horse radish peroxidase, alka
  • Analysis of antigens bound to the antibody arrays can be quantitative, semiquantitative or qualitative.
  • Detect refers to identifying the presence, absence and/or amount of antigen to be detected.
  • Absence of binding, and “lack of detection of product” as used herein includes insignificant or de minimus levels.
  • arrays of uncharacterized antibodies may be used to compare the protein expression profiles of cells, for example, comparisons can be made between a population of cells from one tissue, and a second tissue, or from cells derived from a particular tissue but from different species. Comparisons can be made between normal cells and cells from the same tissue type that originate from an individual with a pathogenic disorder. For example, comparisons can be made between normal cells and cancer cells. Comparisons can additionally be made between cells in a resting state and cells in an activated state.
  • the disclosed arrays are useful for evaluating the expression of proteins by pathogens, such as, for example, bacteria, parasites, viruses, and the like. These antibodies have utility as diagnostic agents as well as potential therapeutics.
  • the systems and methods disclosed herein can be used in methods of diagnosing particular disorders. For example, in a diagnostic kit, a collection of antibodies specific for a range of antigens associated with one or more disorders can be arrayed and contacted with a bodily fluid containing antigens whose presence or absence would indicate a particular disorder.
  • the advantage of using an array over a conventional immunoassay is the ability to include a population of antibodies diagnostic for a variety of disorders on a single surface, significantly reducing time, costs and materials needed to effect a diagnosis.
  • Murine monoclonal antibodies were raised against recombinant human prion proteins. Their specificity for recombinant prion proteins (PRP) including human and bovine was verified by ELISA and western blot. The antibodies were purified in accordance with standard techniques. A total of seven murine monoclonal antibodies against recombinant human PRP were used in the experiments described herein.
  • PRP recombinant prion proteins
  • Antibodies (7A12, 8B4, 2C2, 8H4 and 6H3) are IgGl and antibodies (8F9 and 12H7) are
  • IgG2b Murine monoclonal antibodies against IL-2 and IL-4 were commercially available.
  • Donkey anti-sheep IgG-HRP was purchased from Roche Applied Science
  • the first experiment was intended to demonstrate that the immobilization of antibodies on the solid support does not cause CIq to bind to the immobilized antibodies, and Io show that CIq is able to detect the specific binding of antigens to their antibodies.
  • the experiments described herein were done in accordance with conventional ELlSA assays except for that the second antibody was substituted with CIq. Briefly, the antibodies were diluted in PBS (pH 7.4) to a concentration of 2 ⁇ g/ml. Each well of a 96-well plate was coated with 100 ⁇ l of diluted antibodies (anti-IL2, anti-lL4, and 7A l 2) for 3 hours at room temperature. Then coated wells were blocked with commercial blocking buffer for 1.5 hours at room temperature.
  • PBST PBS with 0.05% Tween-20
  • human CIq was added into each well at concentrations of 2 ⁇ g/ml, 0.2 ⁇ g/ml, 0.02 ⁇ g/ml and O ⁇ g/ml and incubated for three hours at room temperature.
  • sheep anti-human CIq antibodies were added into each well at concentration of 2 ⁇ g/ml and incubated for 1.5 hours at room temperature.

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Abstract

La présente invention propose un système et un procédé pour détecter des antigènes capturés sur une matrice d'anticorps. Le procédé consiste à fournir la matrice d'anticorps ayant au moins deux anticorps, à mettre en contact la matrice d'anticorps avec un échantillon contenant au moins un antigène qui peut être capturé par les anticorps disposés sur la matrice d'anticorps et à détecter au moins un antigène capturé par la matrice d'anticorps avec un agent de détection qui se lie spécifiquement aux anticorps liés à un antigène sur la matrice d'anticorps, de sorte que l'antigène capturé par la matrice d'anticorps peut être détecté indépendamment des structures des antigènes. Dans un mode préféré de réalisation, C1q est utilisé en tant qu'agent de détection pour détecter des anticorps liés à un antigène.
PCT/US2005/019939 2006-11-13 2006-11-13 Système et procédé pour la détection indépendante de la structure d'antigène d'antigènes capturés sur des matrices d'anticorps Ceased WO2008147345A2 (fr)

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US7863004B2 (en) * 2001-12-04 2011-01-04 Wayne State University Neoepitope detection of disease using protein arrays

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