CA1281640C - Antigen bound by two monoclonal antidodies - Google Patents
Antigen bound by two monoclonal antidodiesInfo
- Publication number
- CA1281640C CA1281640C CA000382964A CA382964A CA1281640C CA 1281640 C CA1281640 C CA 1281640C CA 000382964 A CA000382964 A CA 000382964A CA 382964 A CA382964 A CA 382964A CA 1281640 C CA1281640 C CA 1281640C
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- Prior art keywords
- antibody
- process according
- antigen
- labelled
- sample
- Prior art date
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- Expired - Lifetime
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Classifications
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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
- G01N33/58—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving labelled substances
-
- 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
- G01N33/576—Immunoassay; Biospecific binding assay; Materials therefor for hepatitis
-
- 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; monoclonal antibodies per se are classified with their corresponding antigens
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2470/00—Immunochemical assays or immunoassays characterised by the reaction format or reaction type
- G01N2470/04—Sandwich assay format
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
- Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y10S435/00—Chemistry: molecular biology and microbiology
- Y10S435/971—Capture of complex after antigen-antibody reaction
Abstract
Abstract of the Disclosure More rapid and sensitive "two-site" or "sandwich"
immunometric assay techniques are disclosed for determination of the presence and/or concentration of antigenic substances in fluids using monoclonal antibodies as compared to conven-tional assays using polyclonal antibodies. Also described are inhibition assays using complexes of antigens with a monoclonal antibody.
immunometric assay techniques are disclosed for determination of the presence and/or concentration of antigenic substances in fluids using monoclonal antibodies as compared to conven-tional assays using polyclonal antibodies. Also described are inhibition assays using complexes of antigens with a monoclonal antibody.
Description
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IMMUNOMETRIC AND INHIBITION ASSAYS
USING MONOCLONAL ANTIBODIES
This invention relates to methods for detecting and/or determining the concentration of antigenic sub-stances in fluids such as serum. In another aspect it relates to immunometric and inhibition assay techniques.
In yet another aspect it relates to monoclonal anti-bodies.
The determination of the presence or concentration of antigenic substances, for example, those associated with a wide variety of physiological disorders, in serum 10 or other body fluids relies increasingly upon immunoassay techniques. These techniques are based upon formation of a complex between the antigenic substance being assayed and an antibody or antibodies in which one or the other member of the complex may be labelled, for example, by a radioactive element such as 125I, which permits its detection and/or quantitative analysis after separation of the complexed labelled antigen or antibody from uncomplexed labelled antigen or antibody.
In the case of a competition immunoassay technique, 20 the antigenic substance in a sample of fluid being tested for its presence competes with a known quantity of labelled antigen for a limited quantity of antibody binding sites. Thus, the amount of labelled antigen bound to the antibody is inversely proportional to the amount of antigen in the sample. By contrast, immuno-metric assays employ a labelled antibody. In such an assay, the amount of labelled antibody associated with ~,~," --1--~28~640 the complex is proportional to the amount of antigenic substance in the fluid sample.
Immunometric assays have been found to be particu-larly well suited for the detection of polyvalent anti-gens, i.e., antigenic substances that are able to complex with two or more antibodies at the same time. Such assays typically employ a quantity of unlabelled antibody bound to a solid support that is insoluble in the fluid being tested and a quantity of soluble antibody bearing a lO label such as a radioactive isotope that permits detec-tion and/or a quantitative estimate of the amount of the ternary complex formed between solid phase antibody, antigen, and labelled antibody.
In immunometric assays known to the prior art, typically "forward" a~sayæ, in which the antibody bound to the solid phase is first contacted with the sample being tested to extract the antigen from the sample by formation of a binary solid phase antibody: antigen complex, are employed. After a suitable incubation 20 period, the solid support is washed to remove the residue of the fluid sample, including unreacted antigen, if any, and then contacted with a solution containing a known quantity of labelled antibody.
After a second incubation period to permit the labelled antibody to complex with the antigen bound to the solid support through the unlabelled antibody, the solid support is washed a second time to remove the unreacted labelled antibody. In a simple "yes/no" assay to determine whether the antigen is present in the sample 30 being tested, the washed solid support is tested to ~Z8~6~D
detect the presence of labelled antibody, for example, by measuring emitted radiation if the label is a radioactive element. The amount of labelled antibody detected is compared to that for a negative control sample known to be free of the antigen. Detection of labelled antibody in amounts substantially above the background levels indicated by the negative control is interpreted to indicate the presence of the suspect antigen. Quanti-tative determinations can be made by comparing the 10 measure of labelled antibody with that obtained for calibrated samples containing known quantities of the antigen.
This kind of assay is frequently referred to as a "two-site" or "sandwich" assay since the antigen has two antibodies bonded to its surface at different loca-tions. This and related techniques are described by Wide at pp. 199-206 of "Radioimmunoassay Methods, n Edited by Kirkham and Hunter, E. & S. Livingstone, Edinburgh, 1970. An assay based on this technique for the detection 20 of the antigen associated with serum hepatitis using an 5I labelled antibody is described in U.S. Patent 3,867,517.
Despite their great utility, the prior art immuno-,:
~ metric assays have been recognized to be slow procedures, :: :
in part because two washing steps are required andbecause lengthy incubation periods are required to approach equilibrium, i.e., the point at which the amount ~;~ of complex formed does not change with increasing time.
To eliminate at least one of the washing steps 30 associated with this procedure, so-called "simultaneous"
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~ -3-6~0 and "reverse" assays have been proposed. A simultaneous assay involves a single incubation step as the antibody bound to the solid support and the labelled antibody are both added to the sample being tested at the same time.
After the incubation is completed, the solid support is washed to remove the residue of fluid sample and uncom-plexed labelled antibody. The presence of labelled antibody associated with the solid support is then determined as it would be in a conventional "forward"
10 sandwich assay.
A reverse assay involves the stepwise addition first of a solution of labelled antibody to the fluid sample followed by the addition of unlabelled antibody bound to a solid support after a suitable incubation period. After a second incubation, the solid phase is washed in conventional fashion to free it of the residue of the sample being tested and the solution of unreacted labelled antibody. The determination of labelled anti-body associated with the solid support is then determined 20 as in the simultaneous and forward assays.
Both the simultaneous and reverse assay techniques require a sufficient excess amount of solid phase anti-body to bind most or all of the antigen present to avoid a high dose hook effect where artifically negative or low quantitation of antigen is observed at extremely high concentrations of antigen. For this reason, the forward assay has been the approach preferred by the prior art.
That is because ward assay has been the approach prefer-red by the prior art. That is because large amounts of 30 highly purified, active antibody specific to the antigen ~8~640 of interest for preparing a solid phase with sufficient antigen binding capacity is difficult to obtain from the "polyclonal" antibodies used in prior art processes.
When an immunogenic substance is introduced into a living body, the body's immune system reacts by generating antibodies to every site on the immunogen it recognizes.
A large immunogenic protein molecule may have dozens of sites and a foreign cell may have hundreds. Thus, while each antibody producing cell produces antibody specific 10 for a single antigenic site the immune system has genera-ted a specie of specific antibody producing cells for each immunogenic site recognized. In addition, the body has produced relatively large quantities of antibodies to antigens other than the one of interest such that most of the antibody in the polyclonal mixture is not specific for the antigen of interest. Accordingly, the antibodies used in prior immunometric assays are necessarily "poly-clonal n in nature since the antibodies are derived from antisera raised in a conventional manner in animals and 20 their purification is difficult. Methods for affinity purifying such antibodies have generally been time consuming and resulted in low yields and loss of high affinity antibodies.
When employing conventional polyclonal antibody mixtures in the reverse and simultaneous assays, the formation of a "sandwich" comprising the antigen com-plexed by two or more labelled antibodies which complex with the antigen at dlfferent sites is possible. These complexes could remain soluble in the sample being 30 tested, be removed by subsequent washing steps, and not : : :
1~816~0 "counted" when the solid phase is analyzed for solid phase bound labelled antibody. If this happens to a significant extent, sensitivity of the assay is reduced and erroneous results may arise. However, if the unla-belled bound antibody is added to the sample first as in the forward sandwich assay, steric considerations prevent formation of a sandwich comprising the antigen complexed to two or more unlabelled antibodies where labelled antibody is excluded from also binding to the 10 antigen. Accordingly, the antigen is free to react with a labelled antibody molecule. Nevertheless, it has been proposed to use a simultaneous assay for human thyroid stimulating hormone (HTSH) by employing a large excess of the unlabelled antibody bound to a solid phase to mini-mize formation of a soluble complex by soluble labelled antibodies. See Jeong et al., "Comparison of Radioim-munoassay (RIA) with a Unique, Single-Incubation Two-Site Immunoradiometric Assay (IRMA) as Applied to the Deter-mination of Human Thyroid Stimulating Hormone (HTSH),"
20 Bio-Rad Laboratories, 1979.
A variation of a simultaneous assay is described in U.S. 4,174,384. In that assay, separate portions of AntiIgG (Human) are labelled, respectively, with a fluorescing chromophore (fluorescein) and a chromophore (rhodamine) which absorbs light emitted by the fluo-rescein. Both antibodies, in a soluble form, are con-tacted with a sample containing human IgG. Reaction of the Anti-IgG with the IgG may bring the two chromophores close enough together, i.e., within 100 angstroms or 30 less, that the emission of light by the fluorescing 6~0 chromophore is absorbed (quenched) by the other. The percentage of maximum fluorescence for the sample is determined and used as a measure of the amount of IgG in the sample.
It has also been proposed to use a reverse assay for HTSH, hepatitis associated antigen (HA~) and car-cinoembryonic antigen (CEA) by employing a quantity of labelled antibody sufficient to assure a labelled anti-body: antigen complex but insufficient to form a "sand-10 wich" of all the antigen present in a sample. See U.S.Patent No. 4,098,876.
Since all three of the procedures known to the prior art use a polyclonal mixture of antibodies, the potential for cross-reaction with other materials in serum or other fluid than the antigen for which the test is intended is increased. The occurrence of cross-re-activity with other antigens also reduces the sensitivity of the test for the suspect antigen and increases the prospect of a "false-positive" assay. Furthermore, the 20 use of polyclonal antibodies in a simultaneous or reverse ~ assay requires a careful consideration of the amount of labelled antibody used relative to the amount of solid phase antibody and/or antigen present. In the case of using fluorescence quenching, sensitivity is reduced because the minimum spacing between the fluorescing chromophore and the quenching chromophore is not assured when polyclonal antibodies are employed.
In view of these shortcomings, the limitations to the immunometric procedures known to the prior art are 30 readily apparent. The conventional forward assays are ; -7-lZ8~0 accomplished with fewer steps but require large quanti-ties of solid phase specific antibody and are not well suited to determination of small concentrations of antigen since formation of a sandwich of the antigen with a multiple number of labelled antibody molecules competes with formation of the sandwich comprising bound antibody:antigen:labelled antibody or, in the case of using fluorescence quenching, the formation of a sand-wich without pairing of a fluorescent chromophore with a quenching chromophore is possible; and all are subject to misinterpretation of false-positives due to the polyclonal nature of the antibody.
Accordingly, the present invention is directed towards the provision of an improved process for the immunometric assay for antigenic substances, which permits more rapid immunometric assay techniques and more sensitive immunometric assay techniques.
With the present invention, the polyclonal anti-bodies used in an immunometric assay, for example, as the unlabelled antibody bound to a solid support and the antibody used as the soluble labelled antibody or, in the case of assays relying upon fluorescence quenching, the antibodies carrying a fluorescing or quenching chromophore are replaced by two or more monoclonal antibodies.
According to one aspect of the invention, there is provided an improvement in an immunometric assay process .
. - .
~ ` - ,:
~2~3~6~0 to determine the presence or concentration of an anti-genic substance in a fluid sample comprising forming a ternary complex of the antigenic substance, a first antibody and a second antibody bound to the antigen at a different site than the first antibody by contacting the sample with said first and second antibodies, the improvement comprising employing a monoclonal antibody for each of said first and second antibodies.
In a preferred embodiment of the invention, the monoclonal antibody used as the antibody bound to a solid support is the product of a different cell line than is the monoclonal antibody used for the labelled antibody and the two monoclonal antibodies are selected to bind the antigenic substance at sitee remote from each other so a~ to not interfere with the other's binding to the antigen. In the case of fluorescence quenching, the two antibodies are also usually the products of different cell lines and are selected so as to not interfere with the other's binding yet bring the two chromophores close enough together to permit quench-ing of fluorescence, i.e., usually to within about 100 angstroms. The advantages of the present invention, particularly in simultaneous and reverse assays, over prior art methods will become clear after consideration of the accompanying drawings and the following detailed description of the invention.
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, 16~0 Also, according to the present invention, monoclon-al antibodies are employed in inhibition assays. In such assays, a known quantity of an antigen and mono-clonal antibody is contacted with a sample suspected of containing an antigen corresponding to the known antigen added within the monoclonal antibody. The extent to which inhibition of the complex between the antibody and antigen occurs because a complex comprising the monoclonal antibody and antigen from the sample is formed is a measure of the presence and/or amount of antigen in the sample assayed.
Further, according to another aspect of the inven-tion, there is provided a process for the determination of the presQnce or concentration of an antig~nic substancQ in a fluid, comprising the stQps of:
(a) contacting a sample of the fluid with a known quantity o~ added antigenic substance and a monoclonal antibody to the antigenic substance, and ~ b) measuring the inhibition of formation of a complex between the antibody and added antigenic sub-stance by combination of said monoclonal antibody and the antigenic substance in the fluid to form a second complex.
In a preferred embodiment, the antibody and antigen are bound, respectively, to one of the members of a pair of fluorescing and quenching chromophores. Inhibition of the formation of a complex between the labelled ~:
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, -- . . ~ ' . . ~; -: - .. . .: - . ; .
- ... . . . . :
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--antigen and antibody by antigens in the sample being assayed leads to a reduction in quenching and an increase in fluorescence. The extent of the inhibition of quenching is a measure of antigen concentration in the sample. In another preferred embodiment of an inhibition assay, the known antigen and antibody the original compLex are bound to particles, for example, latex particles, of a size which permits agglomerates to form. When a sample suspected of containing antigen is contacted with the antibody and bound antigen, inhibi-tion of agglomerate formation occurs because of complex-ing between the bound antibody and sample antigen which cannot form agglomerates. The reduction in agglomera-tion can be measured using turbidimetric techniques.
According to a further aspect of the invention, there i~ provided a process for the determination of the presence or concentration of an antigenic substance in a fluid, comprising the steps:
(a) contacting a sample of the fluid with a soluble first monoclonal antibody to the antigenic substance in order to form a soluble complex of the antibody and antigenic substance present in the sample, the first monoclonal antibody being labelled;
(b) contacting the soluble complex with a second monoclonal antibody bound at the time of the determin-ation to a solid carrier, the solid carrier being insoluble in the fluid, in order to form an in~oluble ., - .
: . . . . .
: :' .. - - : . , : . , .
l2a~640 lla complex of the first monoclonal antibody, the antigenic substance and the second monoclonal antibody bound to the 801 id carrier;
(c) separating the solid carrier from the fluid sample and unreacted labelled antibody;
(d) measuring either the amount of labelled anti-body associated with the solid carrier or the amount of unreacted labelled antibody; and (e) relating the amount of labelled antibody measured with the amount of labelled antibody measured for a control sample prepared in accordance with steps (a)-(d), the control sample being Xnown to be free of the antigenic substance, to determine the presence of antigenic substancQ in the fluid sample, or relating : 15 the amount of labelled antibody measured with the amount o~ labelled antibody mQasured for samples containing known amounts of antigenic substance prepared in accor-dance with steps (a)-(d) to determine the concentration : of antigenic substance in the fluid sample.
-: 20 According to an additional aspect of the invention, there is provided a process for the determination of the presence of an antigenic substance in a fluid comprising the steps:
a) simultaneously contacting a sample of the .::
~: 25 fluid with first and second monoclonal antibodies to the antigenic substance, the first monoclonal antibody ,~ being labelled and the second monoclonal antibody being 'i~
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llb bound at the time of the determination to a solid carrier insoluble in the fluid, in order to form an insoluble complex of the first monoclonal antibody, the antigenic substance and the second monoclonal antibody;
b) separating the solid carrier from the fluid sample and unreacted labelled antibody;
c) measuring either the amount of labelled antibody associated with the solid carrier or the amount of unreacted labelled antibody; and d) relating the amount of labelled antibody measured with the amount of labelled antibody measured for a control sample prepared in accordance with steps (a)-(c), the control sample being known to be free of the antigenic substance, to determine the presence of antigenic substance in the fluid sample, or relating the amount of labelled antibody measured with the amount of labelled antibody measured for samples containing known amounts of antigenic substance prepared in accor-dance with steps (a)-(d) to determine the concentration of antigenic substance in the fluid sample.
In a yet further aspect of the present invention, there is provided an improvement in an immunometric assay for the determination of the presence or concen-tration of an antigenic substance in a sample of a fluid comprising forming a ternary complex to a first labelled antibody, the antigenic substance, and a second antibody, the second antibody being bound at the ! I ~
~ ~r ~z~
llc time of the determination to a carrier insoluble in the fluid, the improvement comprising employing a mono-clonal antibody for each of the labelled antibody and the antibody bound to a solid carrier.
The present invention also includes a kit for effecting an immunometric assay and, accordingly, yet another aspect of the invention provides an improvement in an immunometric assay kit for the determination of the presence or concentration of an antigenic substance lo in a sample of a fluid comprising reagents for forming a ternary complex to a first labelled antibody, the anti-genic substance, and a second antibody, the second antibody being bound at the time of the determination to a carrier in~oluble in the ~luid, the improvement comprising employing a monoclonal antibody for each of the labelled antibody and the antibody bound to a solid carrier.
Further, the present invention provides a reagent for immunological assay of antigens based on the sand-, - 20 wich method, characterized in that it comprises insolubilized monoclonal antibody and labelled mono-clonal antibody, the monoclonal antibodies respectively being capable of distinguishing and binding to different ~ antigen determinants of an antigen to be assayed.
`~ 25 Additionally, the present invention provides an improved sandwich method for immunolo~ical assay of - antigens wherein the improvement resides in the fact -: . . .
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lld that insolubilized antibody and labelled antibody react simultaneously with an antigen to be assayed, the insolubilizQd antibody and labelled antibody comprising monoclonal antibodies capable of distinguishing and respectively binding to different antigen determinants of the antigen.
Yet further, the present invention provides an improved sandwich method for immunological assay of antigens wherein the improvement resides in the fact that insolubilised antibody and labelled antibody react simultaneously or in several incubation steps with an antigen to be assayed, the insolubilized antibody and labelled antibody comprising monoclonal antibodies capable of distingui~hlng and re~pectively binding to di~ferent antigen determinants of the antigen.
Yet another aspect of the present invention pro-vides a mixture of monoclonal antibodies useful in an enhanced sensitivity assay for detecting an antigen in a sample which comprises an effective assaying amount of each of at least two monoclonal antibodies which bind to different antigenic sites on the antigen and which are capable under appropriate conditions of forming a stable complex which includes the antigen and all of the -~ monoclonal antibodies.
In each of the various aspects of the invention as recited above, it is preferred that each of the mono-~; clonal antibodies ha~ an affinity for the antigen of at ,:~
"~ ~
:
, - . . .
:- ~ .. -., . ,, ~ .
~281640 lle least about lo8 liters/mole and, more preferably an affinity of at least about lO9 liters/mole.
In the Examples which appear below, reference is made to the accompanying drawings, wherein:
Fig. 1 is a graph illustrating the results obtained using polyclonal antibodies in four types of immuno-metric assay for human IgE: and Fig. 2 is a similar graph illustrating the differ-ence in results obtained using monoclonal antibodies in the same four types of immunometric assay for human IgE.
As indicated above, according to the present invention, the polyclonal antibody used in an immuno-metric assay for an antigenic substance is replaced by a monoclonal antibody. Similarly, monoclonal antibodies are used in inhibition assays. The present invention is -- -- -: - ~ . . ,-, - ~: , .- - ~
.
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useful for the determination of the presence and concen-tration of a wide variety of antigenic substances in-cluding polyvalent antigenic substances. Accordingly, as used herein, the term antigen or antigenic substance refers broadly to substances to which antibodies can be produced. Among such substances may be mentioned hap-tens, hormones such as insulin and human thyroid stim-ulating hormone (HTSH), gamma globulins, allergens, viruses, virus subunits, bacteria, toxins such as those 10 associated with tetanus and with animal venoms, and even some drugs. Among the specific antigens which may be assayed by the processes of the present invention may be mentioned carcinoembryonic antigen (CEA), hepatitis A and B, hepatitis Non A - Non B, IgE and alphafetoprotein.
The monoclonal antibodies useful in the present invention are obtained by the process discussed by Milstein and Kohler and reported in Nature 256 495-497, 1975. The details of this process are well known and will not be repeated here. However, basically it in-20 volves injecting a mouse, or other suitable animal, withan immunogen. The mouse is subsequently sacrificed and cells taken from its spleen are fused with myeloma cells. The result is a hybrid cell, referred to as a "hybridoma, n that reproduces in vitro. The population of hybridomas is screened and manipulated so as to isolate individual clones each of which secretes a single anti-body species to the antigen. Each individual antibody species obtained in this way is the product of a single cell from the immune animal generated in response to a ~ .
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specific antigenic site recognized on the immunogenic substance.
When an immunogenic substance is introduced into a living host, the host's immune system responds by producing antibodies to all the recognizable sites on the substance. This "shotgun" approach to producing anti-bodies to combat the invader results in the production of antibodies of differing affinities and specificities for the immunogenic substance. Accordingly, after the 10 different hybridoma cell lines are screened to identify those that produce antibody to the desired antigen, the antibodies produced by the individual hybridoma cell lines are preferably screened to identify those having the highest affinity for the immunogenic substance stimulating their original production before selection for use in the present invention. Selection based on this criterion is believed to help provide the increased sensitivity in the immunometric and inhibition assays of the present invention using monoclonal antibody compared 20 to the polyclonal antibody used in the prior art which, at best, has an affinity for the antigen which is roughly the average of the affinities of all antibodies produced by the immune system. Preferably, the monoclonal anti-body selected will have an affinity compatible with the desired sensitivity and range for the test system under consideration. Preferably the antibody will have an affinity oP at least 108 liters/mole and, more prefer-ably, an affinity of at least about lO9 liters/mole.
Furthermore, those monoclonal antibodies having 30 the highest affinities can be further screened by running :::
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a simulated assay on specimens known to give false positive-results with processes employing conventional polyclonal antibodies to identify those monoclonal antibodies which do not cross-react and give false positive results.
8ecause the two-site immunometric assay relies upon formation of an antibody:antigen:antibody sandwich, -usually two different monoclonal antibodies which do not interfere with the binding of each other to the antigen 10 are selected to be the bound antibody and the soluble labelled antibody or the antibody pair when fluorescence ~uenching is used. Since both are necessary to complete the sandwich, reverse and simultaneous assays can be conducted without concern, for example, that a complex of labelled antibody:antigen:labelled antibody will form which will preclude formation of a complex between the antigen and the antibody bound to the solid phase and therein lies a particular advantage of the present invention. Furthermore, a forward assay can be accom-20 plished without the intermediate washing step since thetwo antibodies bind to two different sites. We refer to such a process as a "fast forward" assay.
However, particularly in the case of a forward assay, the same monoclonal antibody can be used for both ~ the labelled antibody and the antibody b~und to the solid ;~ support when the antigenic substance possesses identical antibody binding sites sufficiently remote from each ~; other to allow more than one antibody molecule to be bound at the same time. In such a system, the addition 30 first of the bound antibody to the sample precludes ~8164~
formation of a sandwich because of steric considera-tions. When the labelled monoclonal antibody is sub-sequently added, it is also able to complex with the antigen bound to unlabelled antibody on the solid phase.
The unlabelled monoclonal antibody used in the process of the present invention to extract the antigenic substance from the sample being tested may be immobilized on any of the common supports used in immunometric assays. Among these may be mentioned filter paper, 10 plastic beads or test tubes made from polyethylene, polystyrene, polypropylene or other suitable material.
Also useful are particulate materials such as agarose, cross-linked dextran, and other polysaccharides.
The techniques for bonding antibodies to such materials are well know to those skilled in the art. For example, antibodies may be bound to polysaccharide polymers using the process described in U.S. Patent No. 3,645,852.
The labelled monoclonal antibody used in the present invention may be provided with the same labels used in 20 prior art immunometric assays. ~mong these may be mentioned fluorogenic labels for detection by fluorimetry as described in U.S. Patent No. 3,940,475 and enzymatic markers as described in U.S. Patent No. 3,654,090. It is presently preferred to label the antibody with a radioiso-tope such as 125I using, for example, the procedure of Hunter and Greenwood, Nature, 144 (1962), page 945 or that of David et al., Biochemistry, Vol. 13, pp.
1014-1021, 1974.
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In a typical assay, the amount of labelled antibody associatPd with the insoluble sandwich complex is deter-mined by examination of the insoluble carrier material by suitable means. However, it is also possible to relate the presence or absence of antigen in the fluid sample being assayed to the amount of labelled antibody which does not react during the assay and remains in soluble form.
The advantages of the present invention in which 10 monoclonal antibodies are used in immunometric assays as compared to polyclonal antibodies are seen by reference to the following example. In this example, four com-parative assays, a simultaneous assay, a reverse assay, a forward assay, and a "fast" forward assay, were run using both monoclonal antibody and polyclonal antibody using a standard serum containing 100 IU/ml of human IgE as the positive sample. Normal horse serum containing no IgE
was used as a negative control.
The polyclonal antibody to IgE used as the labelled 20 antibody in the example was obtained from Pharmacia Diagnostics of Piscataway, New Jersey. The polyclonal antibody bound to the solid support was obtained from Tago, Inc. of Burlingame, California.
Monoclonal antibody to IgE was obtained using the method of Milstein and Kohler discussed above. The two antibodies selected each exhibited an affinity for IgE of greater than 109 liters/mole and did not interfere :
with the other's binding to IgE.
The assays were run using unlabelled antibody bound 30 to agarose by the process of U.S. Patent No. 3,645,852.
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Labelling of antibody was by 125I according to the process of David et al. referred to above. Phosphate buffered saline, pH 7.4, was used to wash all samples.
Example 1) Simultaneous Assay Method -Duplicate samples were run in which 100 ~ of a suspension of antibody immobilized on agarose particles was mixed with 100 ~ of specimen (serum) and 100 ~ of soluble 25I-labelled antibody. This mixture was incubated 10 for the specified times shown in Table I (for polyclonal antibody) and Table II (for monoclonal antibody) set forth below, plus 30 minutes. The extra 30 minutes incubation period was added to equalize this assay method with the other assay methods which required an additional 30 minutes incubation time for a second added reagent.
Following the incubation periods the agarose particles were washed by addition of buffer and centrifuged. After removal of the washing liquid by aspiration, the re-sulting pellet of agarose particles was then counted for 20 bound 125I-labelled antibody. The counts obtained for each of the complexes after the specified incubation time are set forth in Tables I and II.
IMMUNOMETRIC AND INHIBITION ASSAYS
USING MONOCLONAL ANTIBODIES
This invention relates to methods for detecting and/or determining the concentration of antigenic sub-stances in fluids such as serum. In another aspect it relates to immunometric and inhibition assay techniques.
In yet another aspect it relates to monoclonal anti-bodies.
The determination of the presence or concentration of antigenic substances, for example, those associated with a wide variety of physiological disorders, in serum 10 or other body fluids relies increasingly upon immunoassay techniques. These techniques are based upon formation of a complex between the antigenic substance being assayed and an antibody or antibodies in which one or the other member of the complex may be labelled, for example, by a radioactive element such as 125I, which permits its detection and/or quantitative analysis after separation of the complexed labelled antigen or antibody from uncomplexed labelled antigen or antibody.
In the case of a competition immunoassay technique, 20 the antigenic substance in a sample of fluid being tested for its presence competes with a known quantity of labelled antigen for a limited quantity of antibody binding sites. Thus, the amount of labelled antigen bound to the antibody is inversely proportional to the amount of antigen in the sample. By contrast, immuno-metric assays employ a labelled antibody. In such an assay, the amount of labelled antibody associated with ~,~," --1--~28~640 the complex is proportional to the amount of antigenic substance in the fluid sample.
Immunometric assays have been found to be particu-larly well suited for the detection of polyvalent anti-gens, i.e., antigenic substances that are able to complex with two or more antibodies at the same time. Such assays typically employ a quantity of unlabelled antibody bound to a solid support that is insoluble in the fluid being tested and a quantity of soluble antibody bearing a lO label such as a radioactive isotope that permits detec-tion and/or a quantitative estimate of the amount of the ternary complex formed between solid phase antibody, antigen, and labelled antibody.
In immunometric assays known to the prior art, typically "forward" a~sayæ, in which the antibody bound to the solid phase is first contacted with the sample being tested to extract the antigen from the sample by formation of a binary solid phase antibody: antigen complex, are employed. After a suitable incubation 20 period, the solid support is washed to remove the residue of the fluid sample, including unreacted antigen, if any, and then contacted with a solution containing a known quantity of labelled antibody.
After a second incubation period to permit the labelled antibody to complex with the antigen bound to the solid support through the unlabelled antibody, the solid support is washed a second time to remove the unreacted labelled antibody. In a simple "yes/no" assay to determine whether the antigen is present in the sample 30 being tested, the washed solid support is tested to ~Z8~6~D
detect the presence of labelled antibody, for example, by measuring emitted radiation if the label is a radioactive element. The amount of labelled antibody detected is compared to that for a negative control sample known to be free of the antigen. Detection of labelled antibody in amounts substantially above the background levels indicated by the negative control is interpreted to indicate the presence of the suspect antigen. Quanti-tative determinations can be made by comparing the 10 measure of labelled antibody with that obtained for calibrated samples containing known quantities of the antigen.
This kind of assay is frequently referred to as a "two-site" or "sandwich" assay since the antigen has two antibodies bonded to its surface at different loca-tions. This and related techniques are described by Wide at pp. 199-206 of "Radioimmunoassay Methods, n Edited by Kirkham and Hunter, E. & S. Livingstone, Edinburgh, 1970. An assay based on this technique for the detection 20 of the antigen associated with serum hepatitis using an 5I labelled antibody is described in U.S. Patent 3,867,517.
Despite their great utility, the prior art immuno-,:
~ metric assays have been recognized to be slow procedures, :: :
in part because two washing steps are required andbecause lengthy incubation periods are required to approach equilibrium, i.e., the point at which the amount ~;~ of complex formed does not change with increasing time.
To eliminate at least one of the washing steps 30 associated with this procedure, so-called "simultaneous"
:: .
~ -3-6~0 and "reverse" assays have been proposed. A simultaneous assay involves a single incubation step as the antibody bound to the solid support and the labelled antibody are both added to the sample being tested at the same time.
After the incubation is completed, the solid support is washed to remove the residue of fluid sample and uncom-plexed labelled antibody. The presence of labelled antibody associated with the solid support is then determined as it would be in a conventional "forward"
10 sandwich assay.
A reverse assay involves the stepwise addition first of a solution of labelled antibody to the fluid sample followed by the addition of unlabelled antibody bound to a solid support after a suitable incubation period. After a second incubation, the solid phase is washed in conventional fashion to free it of the residue of the sample being tested and the solution of unreacted labelled antibody. The determination of labelled anti-body associated with the solid support is then determined 20 as in the simultaneous and forward assays.
Both the simultaneous and reverse assay techniques require a sufficient excess amount of solid phase anti-body to bind most or all of the antigen present to avoid a high dose hook effect where artifically negative or low quantitation of antigen is observed at extremely high concentrations of antigen. For this reason, the forward assay has been the approach preferred by the prior art.
That is because ward assay has been the approach prefer-red by the prior art. That is because large amounts of 30 highly purified, active antibody specific to the antigen ~8~640 of interest for preparing a solid phase with sufficient antigen binding capacity is difficult to obtain from the "polyclonal" antibodies used in prior art processes.
When an immunogenic substance is introduced into a living body, the body's immune system reacts by generating antibodies to every site on the immunogen it recognizes.
A large immunogenic protein molecule may have dozens of sites and a foreign cell may have hundreds. Thus, while each antibody producing cell produces antibody specific 10 for a single antigenic site the immune system has genera-ted a specie of specific antibody producing cells for each immunogenic site recognized. In addition, the body has produced relatively large quantities of antibodies to antigens other than the one of interest such that most of the antibody in the polyclonal mixture is not specific for the antigen of interest. Accordingly, the antibodies used in prior immunometric assays are necessarily "poly-clonal n in nature since the antibodies are derived from antisera raised in a conventional manner in animals and 20 their purification is difficult. Methods for affinity purifying such antibodies have generally been time consuming and resulted in low yields and loss of high affinity antibodies.
When employing conventional polyclonal antibody mixtures in the reverse and simultaneous assays, the formation of a "sandwich" comprising the antigen com-plexed by two or more labelled antibodies which complex with the antigen at dlfferent sites is possible. These complexes could remain soluble in the sample being 30 tested, be removed by subsequent washing steps, and not : : :
1~816~0 "counted" when the solid phase is analyzed for solid phase bound labelled antibody. If this happens to a significant extent, sensitivity of the assay is reduced and erroneous results may arise. However, if the unla-belled bound antibody is added to the sample first as in the forward sandwich assay, steric considerations prevent formation of a sandwich comprising the antigen complexed to two or more unlabelled antibodies where labelled antibody is excluded from also binding to the 10 antigen. Accordingly, the antigen is free to react with a labelled antibody molecule. Nevertheless, it has been proposed to use a simultaneous assay for human thyroid stimulating hormone (HTSH) by employing a large excess of the unlabelled antibody bound to a solid phase to mini-mize formation of a soluble complex by soluble labelled antibodies. See Jeong et al., "Comparison of Radioim-munoassay (RIA) with a Unique, Single-Incubation Two-Site Immunoradiometric Assay (IRMA) as Applied to the Deter-mination of Human Thyroid Stimulating Hormone (HTSH),"
20 Bio-Rad Laboratories, 1979.
A variation of a simultaneous assay is described in U.S. 4,174,384. In that assay, separate portions of AntiIgG (Human) are labelled, respectively, with a fluorescing chromophore (fluorescein) and a chromophore (rhodamine) which absorbs light emitted by the fluo-rescein. Both antibodies, in a soluble form, are con-tacted with a sample containing human IgG. Reaction of the Anti-IgG with the IgG may bring the two chromophores close enough together, i.e., within 100 angstroms or 30 less, that the emission of light by the fluorescing 6~0 chromophore is absorbed (quenched) by the other. The percentage of maximum fluorescence for the sample is determined and used as a measure of the amount of IgG in the sample.
It has also been proposed to use a reverse assay for HTSH, hepatitis associated antigen (HA~) and car-cinoembryonic antigen (CEA) by employing a quantity of labelled antibody sufficient to assure a labelled anti-body: antigen complex but insufficient to form a "sand-10 wich" of all the antigen present in a sample. See U.S.Patent No. 4,098,876.
Since all three of the procedures known to the prior art use a polyclonal mixture of antibodies, the potential for cross-reaction with other materials in serum or other fluid than the antigen for which the test is intended is increased. The occurrence of cross-re-activity with other antigens also reduces the sensitivity of the test for the suspect antigen and increases the prospect of a "false-positive" assay. Furthermore, the 20 use of polyclonal antibodies in a simultaneous or reverse ~ assay requires a careful consideration of the amount of labelled antibody used relative to the amount of solid phase antibody and/or antigen present. In the case of using fluorescence quenching, sensitivity is reduced because the minimum spacing between the fluorescing chromophore and the quenching chromophore is not assured when polyclonal antibodies are employed.
In view of these shortcomings, the limitations to the immunometric procedures known to the prior art are 30 readily apparent. The conventional forward assays are ; -7-lZ8~0 accomplished with fewer steps but require large quanti-ties of solid phase specific antibody and are not well suited to determination of small concentrations of antigen since formation of a sandwich of the antigen with a multiple number of labelled antibody molecules competes with formation of the sandwich comprising bound antibody:antigen:labelled antibody or, in the case of using fluorescence quenching, the formation of a sand-wich without pairing of a fluorescent chromophore with a quenching chromophore is possible; and all are subject to misinterpretation of false-positives due to the polyclonal nature of the antibody.
Accordingly, the present invention is directed towards the provision of an improved process for the immunometric assay for antigenic substances, which permits more rapid immunometric assay techniques and more sensitive immunometric assay techniques.
With the present invention, the polyclonal anti-bodies used in an immunometric assay, for example, as the unlabelled antibody bound to a solid support and the antibody used as the soluble labelled antibody or, in the case of assays relying upon fluorescence quenching, the antibodies carrying a fluorescing or quenching chromophore are replaced by two or more monoclonal antibodies.
According to one aspect of the invention, there is provided an improvement in an immunometric assay process .
. - .
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~2~3~6~0 to determine the presence or concentration of an anti-genic substance in a fluid sample comprising forming a ternary complex of the antigenic substance, a first antibody and a second antibody bound to the antigen at a different site than the first antibody by contacting the sample with said first and second antibodies, the improvement comprising employing a monoclonal antibody for each of said first and second antibodies.
In a preferred embodiment of the invention, the monoclonal antibody used as the antibody bound to a solid support is the product of a different cell line than is the monoclonal antibody used for the labelled antibody and the two monoclonal antibodies are selected to bind the antigenic substance at sitee remote from each other so a~ to not interfere with the other's binding to the antigen. In the case of fluorescence quenching, the two antibodies are also usually the products of different cell lines and are selected so as to not interfere with the other's binding yet bring the two chromophores close enough together to permit quench-ing of fluorescence, i.e., usually to within about 100 angstroms. The advantages of the present invention, particularly in simultaneous and reverse assays, over prior art methods will become clear after consideration of the accompanying drawings and the following detailed description of the invention.
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, 16~0 Also, according to the present invention, monoclon-al antibodies are employed in inhibition assays. In such assays, a known quantity of an antigen and mono-clonal antibody is contacted with a sample suspected of containing an antigen corresponding to the known antigen added within the monoclonal antibody. The extent to which inhibition of the complex between the antibody and antigen occurs because a complex comprising the monoclonal antibody and antigen from the sample is formed is a measure of the presence and/or amount of antigen in the sample assayed.
Further, according to another aspect of the inven-tion, there is provided a process for the determination of the presQnce or concentration of an antig~nic substancQ in a fluid, comprising the stQps of:
(a) contacting a sample of the fluid with a known quantity o~ added antigenic substance and a monoclonal antibody to the antigenic substance, and ~ b) measuring the inhibition of formation of a complex between the antibody and added antigenic sub-stance by combination of said monoclonal antibody and the antigenic substance in the fluid to form a second complex.
In a preferred embodiment, the antibody and antigen are bound, respectively, to one of the members of a pair of fluorescing and quenching chromophores. Inhibition of the formation of a complex between the labelled ~:
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--antigen and antibody by antigens in the sample being assayed leads to a reduction in quenching and an increase in fluorescence. The extent of the inhibition of quenching is a measure of antigen concentration in the sample. In another preferred embodiment of an inhibition assay, the known antigen and antibody the original compLex are bound to particles, for example, latex particles, of a size which permits agglomerates to form. When a sample suspected of containing antigen is contacted with the antibody and bound antigen, inhibi-tion of agglomerate formation occurs because of complex-ing between the bound antibody and sample antigen which cannot form agglomerates. The reduction in agglomera-tion can be measured using turbidimetric techniques.
According to a further aspect of the invention, there i~ provided a process for the determination of the presence or concentration of an antigenic substance in a fluid, comprising the steps:
(a) contacting a sample of the fluid with a soluble first monoclonal antibody to the antigenic substance in order to form a soluble complex of the antibody and antigenic substance present in the sample, the first monoclonal antibody being labelled;
(b) contacting the soluble complex with a second monoclonal antibody bound at the time of the determin-ation to a solid carrier, the solid carrier being insoluble in the fluid, in order to form an in~oluble ., - .
: . . . . .
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l2a~640 lla complex of the first monoclonal antibody, the antigenic substance and the second monoclonal antibody bound to the 801 id carrier;
(c) separating the solid carrier from the fluid sample and unreacted labelled antibody;
(d) measuring either the amount of labelled anti-body associated with the solid carrier or the amount of unreacted labelled antibody; and (e) relating the amount of labelled antibody measured with the amount of labelled antibody measured for a control sample prepared in accordance with steps (a)-(d), the control sample being Xnown to be free of the antigenic substance, to determine the presence of antigenic substancQ in the fluid sample, or relating : 15 the amount of labelled antibody measured with the amount o~ labelled antibody mQasured for samples containing known amounts of antigenic substance prepared in accor-dance with steps (a)-(d) to determine the concentration : of antigenic substance in the fluid sample.
-: 20 According to an additional aspect of the invention, there is provided a process for the determination of the presence of an antigenic substance in a fluid comprising the steps:
a) simultaneously contacting a sample of the .::
~: 25 fluid with first and second monoclonal antibodies to the antigenic substance, the first monoclonal antibody ,~ being labelled and the second monoclonal antibody being 'i~
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llb bound at the time of the determination to a solid carrier insoluble in the fluid, in order to form an insoluble complex of the first monoclonal antibody, the antigenic substance and the second monoclonal antibody;
b) separating the solid carrier from the fluid sample and unreacted labelled antibody;
c) measuring either the amount of labelled antibody associated with the solid carrier or the amount of unreacted labelled antibody; and d) relating the amount of labelled antibody measured with the amount of labelled antibody measured for a control sample prepared in accordance with steps (a)-(c), the control sample being known to be free of the antigenic substance, to determine the presence of antigenic substance in the fluid sample, or relating the amount of labelled antibody measured with the amount of labelled antibody measured for samples containing known amounts of antigenic substance prepared in accor-dance with steps (a)-(d) to determine the concentration of antigenic substance in the fluid sample.
In a yet further aspect of the present invention, there is provided an improvement in an immunometric assay for the determination of the presence or concen-tration of an antigenic substance in a sample of a fluid comprising forming a ternary complex to a first labelled antibody, the antigenic substance, and a second antibody, the second antibody being bound at the ! I ~
~ ~r ~z~
llc time of the determination to a carrier insoluble in the fluid, the improvement comprising employing a mono-clonal antibody for each of the labelled antibody and the antibody bound to a solid carrier.
The present invention also includes a kit for effecting an immunometric assay and, accordingly, yet another aspect of the invention provides an improvement in an immunometric assay kit for the determination of the presence or concentration of an antigenic substance lo in a sample of a fluid comprising reagents for forming a ternary complex to a first labelled antibody, the anti-genic substance, and a second antibody, the second antibody being bound at the time of the determination to a carrier in~oluble in the ~luid, the improvement comprising employing a monoclonal antibody for each of the labelled antibody and the antibody bound to a solid carrier.
Further, the present invention provides a reagent for immunological assay of antigens based on the sand-, - 20 wich method, characterized in that it comprises insolubilized monoclonal antibody and labelled mono-clonal antibody, the monoclonal antibodies respectively being capable of distinguishing and binding to different ~ antigen determinants of an antigen to be assayed.
`~ 25 Additionally, the present invention provides an improved sandwich method for immunolo~ical assay of - antigens wherein the improvement resides in the fact -: . . .
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lld that insolubilized antibody and labelled antibody react simultaneously with an antigen to be assayed, the insolubilizQd antibody and labelled antibody comprising monoclonal antibodies capable of distinguishing and respectively binding to different antigen determinants of the antigen.
Yet further, the present invention provides an improved sandwich method for immunological assay of antigens wherein the improvement resides in the fact that insolubilised antibody and labelled antibody react simultaneously or in several incubation steps with an antigen to be assayed, the insolubilized antibody and labelled antibody comprising monoclonal antibodies capable of distingui~hlng and re~pectively binding to di~ferent antigen determinants of the antigen.
Yet another aspect of the present invention pro-vides a mixture of monoclonal antibodies useful in an enhanced sensitivity assay for detecting an antigen in a sample which comprises an effective assaying amount of each of at least two monoclonal antibodies which bind to different antigenic sites on the antigen and which are capable under appropriate conditions of forming a stable complex which includes the antigen and all of the -~ monoclonal antibodies.
In each of the various aspects of the invention as recited above, it is preferred that each of the mono-~; clonal antibodies ha~ an affinity for the antigen of at ,:~
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~281640 lle least about lo8 liters/mole and, more preferably an affinity of at least about lO9 liters/mole.
In the Examples which appear below, reference is made to the accompanying drawings, wherein:
Fig. 1 is a graph illustrating the results obtained using polyclonal antibodies in four types of immuno-metric assay for human IgE: and Fig. 2 is a similar graph illustrating the differ-ence in results obtained using monoclonal antibodies in the same four types of immunometric assay for human IgE.
As indicated above, according to the present invention, the polyclonal antibody used in an immuno-metric assay for an antigenic substance is replaced by a monoclonal antibody. Similarly, monoclonal antibodies are used in inhibition assays. The present invention is -- -- -: - ~ . . ,-, - ~: , .- - ~
.
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useful for the determination of the presence and concen-tration of a wide variety of antigenic substances in-cluding polyvalent antigenic substances. Accordingly, as used herein, the term antigen or antigenic substance refers broadly to substances to which antibodies can be produced. Among such substances may be mentioned hap-tens, hormones such as insulin and human thyroid stim-ulating hormone (HTSH), gamma globulins, allergens, viruses, virus subunits, bacteria, toxins such as those 10 associated with tetanus and with animal venoms, and even some drugs. Among the specific antigens which may be assayed by the processes of the present invention may be mentioned carcinoembryonic antigen (CEA), hepatitis A and B, hepatitis Non A - Non B, IgE and alphafetoprotein.
The monoclonal antibodies useful in the present invention are obtained by the process discussed by Milstein and Kohler and reported in Nature 256 495-497, 1975. The details of this process are well known and will not be repeated here. However, basically it in-20 volves injecting a mouse, or other suitable animal, withan immunogen. The mouse is subsequently sacrificed and cells taken from its spleen are fused with myeloma cells. The result is a hybrid cell, referred to as a "hybridoma, n that reproduces in vitro. The population of hybridomas is screened and manipulated so as to isolate individual clones each of which secretes a single anti-body species to the antigen. Each individual antibody species obtained in this way is the product of a single cell from the immune animal generated in response to a ~ .
~ ~ .
1~
specific antigenic site recognized on the immunogenic substance.
When an immunogenic substance is introduced into a living host, the host's immune system responds by producing antibodies to all the recognizable sites on the substance. This "shotgun" approach to producing anti-bodies to combat the invader results in the production of antibodies of differing affinities and specificities for the immunogenic substance. Accordingly, after the 10 different hybridoma cell lines are screened to identify those that produce antibody to the desired antigen, the antibodies produced by the individual hybridoma cell lines are preferably screened to identify those having the highest affinity for the immunogenic substance stimulating their original production before selection for use in the present invention. Selection based on this criterion is believed to help provide the increased sensitivity in the immunometric and inhibition assays of the present invention using monoclonal antibody compared 20 to the polyclonal antibody used in the prior art which, at best, has an affinity for the antigen which is roughly the average of the affinities of all antibodies produced by the immune system. Preferably, the monoclonal anti-body selected will have an affinity compatible with the desired sensitivity and range for the test system under consideration. Preferably the antibody will have an affinity oP at least 108 liters/mole and, more prefer-ably, an affinity of at least about lO9 liters/mole.
Furthermore, those monoclonal antibodies having 30 the highest affinities can be further screened by running :::
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a simulated assay on specimens known to give false positive-results with processes employing conventional polyclonal antibodies to identify those monoclonal antibodies which do not cross-react and give false positive results.
8ecause the two-site immunometric assay relies upon formation of an antibody:antigen:antibody sandwich, -usually two different monoclonal antibodies which do not interfere with the binding of each other to the antigen 10 are selected to be the bound antibody and the soluble labelled antibody or the antibody pair when fluorescence ~uenching is used. Since both are necessary to complete the sandwich, reverse and simultaneous assays can be conducted without concern, for example, that a complex of labelled antibody:antigen:labelled antibody will form which will preclude formation of a complex between the antigen and the antibody bound to the solid phase and therein lies a particular advantage of the present invention. Furthermore, a forward assay can be accom-20 plished without the intermediate washing step since thetwo antibodies bind to two different sites. We refer to such a process as a "fast forward" assay.
However, particularly in the case of a forward assay, the same monoclonal antibody can be used for both ~ the labelled antibody and the antibody b~und to the solid ;~ support when the antigenic substance possesses identical antibody binding sites sufficiently remote from each ~; other to allow more than one antibody molecule to be bound at the same time. In such a system, the addition 30 first of the bound antibody to the sample precludes ~8164~
formation of a sandwich because of steric considera-tions. When the labelled monoclonal antibody is sub-sequently added, it is also able to complex with the antigen bound to unlabelled antibody on the solid phase.
The unlabelled monoclonal antibody used in the process of the present invention to extract the antigenic substance from the sample being tested may be immobilized on any of the common supports used in immunometric assays. Among these may be mentioned filter paper, 10 plastic beads or test tubes made from polyethylene, polystyrene, polypropylene or other suitable material.
Also useful are particulate materials such as agarose, cross-linked dextran, and other polysaccharides.
The techniques for bonding antibodies to such materials are well know to those skilled in the art. For example, antibodies may be bound to polysaccharide polymers using the process described in U.S. Patent No. 3,645,852.
The labelled monoclonal antibody used in the present invention may be provided with the same labels used in 20 prior art immunometric assays. ~mong these may be mentioned fluorogenic labels for detection by fluorimetry as described in U.S. Patent No. 3,940,475 and enzymatic markers as described in U.S. Patent No. 3,654,090. It is presently preferred to label the antibody with a radioiso-tope such as 125I using, for example, the procedure of Hunter and Greenwood, Nature, 144 (1962), page 945 or that of David et al., Biochemistry, Vol. 13, pp.
1014-1021, 1974.
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In a typical assay, the amount of labelled antibody associatPd with the insoluble sandwich complex is deter-mined by examination of the insoluble carrier material by suitable means. However, it is also possible to relate the presence or absence of antigen in the fluid sample being assayed to the amount of labelled antibody which does not react during the assay and remains in soluble form.
The advantages of the present invention in which 10 monoclonal antibodies are used in immunometric assays as compared to polyclonal antibodies are seen by reference to the following example. In this example, four com-parative assays, a simultaneous assay, a reverse assay, a forward assay, and a "fast" forward assay, were run using both monoclonal antibody and polyclonal antibody using a standard serum containing 100 IU/ml of human IgE as the positive sample. Normal horse serum containing no IgE
was used as a negative control.
The polyclonal antibody to IgE used as the labelled 20 antibody in the example was obtained from Pharmacia Diagnostics of Piscataway, New Jersey. The polyclonal antibody bound to the solid support was obtained from Tago, Inc. of Burlingame, California.
Monoclonal antibody to IgE was obtained using the method of Milstein and Kohler discussed above. The two antibodies selected each exhibited an affinity for IgE of greater than 109 liters/mole and did not interfere :
with the other's binding to IgE.
The assays were run using unlabelled antibody bound 30 to agarose by the process of U.S. Patent No. 3,645,852.
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Labelling of antibody was by 125I according to the process of David et al. referred to above. Phosphate buffered saline, pH 7.4, was used to wash all samples.
Example 1) Simultaneous Assay Method -Duplicate samples were run in which 100 ~ of a suspension of antibody immobilized on agarose particles was mixed with 100 ~ of specimen (serum) and 100 ~ of soluble 25I-labelled antibody. This mixture was incubated 10 for the specified times shown in Table I (for polyclonal antibody) and Table II (for monoclonal antibody) set forth below, plus 30 minutes. The extra 30 minutes incubation period was added to equalize this assay method with the other assay methods which required an additional 30 minutes incubation time for a second added reagent.
Following the incubation periods the agarose particles were washed by addition of buffer and centrifuged. After removal of the washing liquid by aspiration, the re-sulting pellet of agarose particles was then counted for 20 bound 125I-labelled antibody. The counts obtained for each of the complexes after the specified incubation time are set forth in Tables I and II.
2) Reverse Assay Method -Duplicate samples were run in which 100 ~ of specimen (serum) was mixed with 100 ~ of 125I-labelled soluble antibody and incubated for the specified times shown in Tables I and II. 100 ~ of a suspension of antibody immobilized on agarose particles is then added and the mixture was allowed to incubate for another 30 minutes.
30 The agarose particles were then washed and counted as in ~:
~28~
the simultaneous assay method. The counts are reported in Tables I and II.
30 The agarose particles were then washed and counted as in ~:
~28~
the simultaneous assay method. The counts are reported in Tables I and II.
3) Forward Assay Method -Duplicate samples were run in which 100 ~ of specimen (serum) was mixed with 100 ~ of a suspension of antibody immobilized on agarose particles and incubated for the specified times shown in Tables I and II. The agarose particles were then washed once by the addition of 2.5-3.0 ml of buffer which, after mixing, was centri-10 fuged, and the liquid removed by aspiration. 100 ,ulof I-labelled soluble antibody was then added and the mixture incubated an additional 30 minutes. The agarose particles were then washed and counted as in the simultaneous assay method. The counts are reported in Tables I and II.
4) Fast Forward Assay Method -The assay was performed, in duplicate, in a similar manner to the forward assay method except that the wash step between the initial incubation of specimen with 20 antibody immobilized on agarose particles and the addition of soluble 125I-labeled antibody was omit-ted.
The counts/minute for the duplicate controls and the duplicate assays of the samples containing IgE using polyclonal antibody and monoclonal antibody are shown in Tables I and II, respectively. These data were used to prepare Figures I and II in the following way. The average of the counts/minute for a control for a given incubation period was subtracted from the average of the ~; 30 counts for the corresponding IgE assay. The difference , was calculated as a percentage of the total counts/
minute of labelled antibody added to the sample and is plotted on the Y axis as the percentage of total counts/
minute of antibody bound to the solid phase. The incuba-tion time is plotted on the X axis.
A comparison of the plots shown in Figure 2 dis-playing the results of assays using monoclonal antibody with those of Figure 1 of assays using using polyclonal antibody shows that in êach kind of assay, simultaneous, 10 reverse, forward, and fast forward, the assay using monoclonal antibody was more sensitive as indicated by the higher percentage of total counts bound to the solid phase with 100 IU IgE/ml specimen. Unexpectedly, in the case of the simultaneous and reverse assays, we have found that those run with monoclonal antibody reach equilibrium more rapidly than does the corresponding assay using polyclonal antibody. Therefore, by using a monoclonal antibody in these procedures, the time for the assay can be reduced significantly beyond the time saving 20 achieved by merely eliminating a washing step. In that regard, the reverse assay with monoclonal antibody reached equilibrium in less than one hour. The same assay run with polyclonal assay did not reach eguilibrium until after 4 hours. Similarly, in the case of simulta-neous assays, the assay using monoclonal antibody reached equilibrium within 8 hours whereas the assay with poly-clonal antibody did not reach equilibrium within 24 hours. Accordingly, the present invention provides substantially more rapid and sensitive simultaneous and reverse assays than the prior art processes and elimi-nates the concern that formation of a soluble "sandwich"
complex will compete with formation of the desired insoluble complex.
In the foregoing discussion, the focus has been upon two site or sandwich assays in which one of the antibodies is insolubilized while the other is soluble in the medium analyzed. Other variations are possible. A
preferred variant employs antibodies bound to particles, 10 such as particles of latex, in a manner which results in each particle carrying a plurality of antibodies. When a quantity of particles to which a first monoclonal anti-body is bound is admixed with, for example, quantity of particles to which a second monoclonal antibody is bound, a milky suspension results. However, if a sample con-taining polyvalent antigen for which the antibodies are specific is introduced to the suspension, agglomeration or agglutination of the particles will occur to form easily detectable particle clumps.
The visual detection of agglomerate formation can be used in a screening test for presence of the antigen.
This detection can be aided by coloring the particles carrying one monoclonal antibody differently from the particle carrying the other. However, the extent of agglomeration can also be determined as a measure of the amount of antigen present in the sample. For example, the change in turbidity can be measured using standard techniques such as nephelometry.
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128~640 It is presently preferred to use latex particles to which the antibody is covalently bound using techniques well known to those skilled in the art. However, other particulate supports can be used. Among these may be mentioned silica, glass, cells, polyacrylamides, poly-methyl methacrylate and agarose. Preferably, the par-ticles vary in size between about 0.2~ to about 10~.
Visual screening, however, requires particles of at least about 1.0~.
In yet another variant, one of the antibodies is insolubilized on a bead, test tube wall or other macro-scopic solid suport, and the other is bound to small particles of latex or other suitable material. In the presence of antigen, a sandwich of the antigen between the macroscopically bound antibody and the particle bound antibody will form. By, for example, coloring the particles, formation of the sandwich can be determined visually. A fluorescent, enzymatic, radioactive or other label on the particle bound antibody can be used for 20 quantitative determinations just as in the case of using a soluble antibody described above.
In another preferred variant of the two-site assay, at least one of two different monoclonal antibodies is bound to an enzyme which catalyzes a reaction involving a substance bound to the other monoclonal antibody to produce either a detectable substance or in some other way interacts with the substance on the second antibody to permit detection of the antibody:antigen:antibody complex. Detection may be, for example, by colorimetry, 30 fluorimetry, luminescence, spectrophotometry, or the :, .
12816~0 like. It will be appreciated that, using such techniques, neither antibody needs to be insolubilized, greatly simplifying the assay.
In a presently preferred embodiment, the substance on the second antibody is also an enzyme and the assay employs the pair of enzyme labelled antibodies to cat-alyze sequential reactions, one of which produces a product required by the other. In those reactions, the two antibodies are selected so that when they bind with 10 the antigen, they are sterically positioned so that the product of the first enzymatic reaction is generated in such close proximity to the second enzyme labelled antibody, that the second reaction occurs before signif-icant diffusion of the product of the first reaction into the surrounding medium can take place.
This process can be illustrated using a pair of monoclonal antibodies, one of which is labelled with hexokinase (HK), the other with glucose-6-phosphate dehydrogenase (G-6-PDH), in the following series of 20 reactions.
HK
(1) adenosine triphosphate + glucose r (ATP) adenosine diphosphate + glucose-6-phosphate (ADP) 1~8~6~0 (2) glucose-6-phosphate + nicotinamide adenine dinucleotide (NAD+) ~ gluconolactone-6-phosphate +
dihydronicotinamide adenine dinucleotide (NADH) The assay is conducted by adding to the sample containing the suspect antigen the labelled antibodies to 10 the antigen, ATP, glucose and the coenzyme NAD+. If the antigen is present, a complex as illustrated below is formed:
- Ab(~K) Ag - Ab(G-6-PDH) The HK labelled antibody catalyzes the formation of glucose-6-phosphate in proximity to the G-6-PDH labelled antibody where it is converted to gluconolactone-6-phos-phate. The NADH formed in this reactio~ by reduction of 20 NAD+ can be detected spectrophometrically because of the strong absorption at 340 nm characteristic of a dihydronicotinamide.
The same conversion of glucose to gluconolactone-6-phosphate with formation of NADH also may occur in the medium itself catalyzed by the uncomplexed labelled antibodies, but at a much slower rate than when the two antibodies are positioned near each other in the anti-body:antigen:antibody complex. Accordingly, an increase of absorption at 340 nm compared to a control sample 30 confirms the presence of antigen in the sample. The ,, .
~2~
increase in absorption can also be corelated to the quantity of antigen in the complex.
Any other pair of suitable sequential enzymatically catalyzed reactions may be used in a two-site assay with appropriately labelled antibodies to a suspect antigen.
Among those may be mentioned the reaction of glucose catalyzed with glucose oxidase to form glucono-~-lactone and hydrogen peroxide followed by the reaction of the hydrogen peroxide with ophenylenediamine catalyzed by 10 peroxidase to produce a colored moiety. In this assay, one of the monoclonal antibodies is labelled with glucose oxidase and the other with peroxidase. The intensity of the color produced compared to a control can be corre-lated to the presence and/or amount of antigen in the sample assayed. It will be appreciated that other substances oxidizable to a colored moiety in the presence of an enzyme can be substituted for o-phenylenediamine.
Yet another suitable pair of sequential reactions using a pair of antibodies to a desired antigen labelled, 20 respectively, with NAD oxidoreductase and luciferase is the following:
NAD oxido-reductase (1) NADH + riboflavin-5'-phosphate (FMN) FMNH2 + NAD+
luciferase (2) FMNH2 + RCHO + 2 FMN* + RCOOH + H2O
RCHO is typically a straight chain aldehyde of 10 or more 30 carbon atoms.
.:
12816~0 The generation of FMN*, an excited state of FMN, is followed by the emission of a photon which can be detec-ted photometrically for correlation with a control sample to indicate the presence and/or quantity of antigen in a sample being assayed.
In another embodiment using a pair of antibodies labelled with enzymes, the product of the first enzymat-ically catalyzed reaction can be either an allosteric activator or inhibitor of the subsequent enzyme catalyzed 10 reaction. An allosteric activator, rather than being consumed in the second reaction, interacts with the enzyme to increase its affinity for a substrate or to increase the rate of conversion of the substrate to product after the enzyme-substrate complex is formed.
Allosteric inhibitors, on the other hand, have the opposite effect and reduce the enzyme's affinity for a substrate or reduce the rate of conversion of substrate to product. Allosteric inhibition may be of the compet-itive or non-competitive type.
An example of an assay involving allosteric activa-tion employing a pair of antibodies labelled, respec-tively, with phosphofructokinase and phosphoenolpyruvate uses the following reaction scheme:
phosphofructokinase (1) fructose-6-phosphate + ATP
fructose-1,6-diphosphate + ADP
12Bl~O
(2) HCO3- + phosphoenolpyruvate (PEP) phosphoenolpyruvate carboxylase - ~ oxaloacetate (OAA) malate dehydrogenase (3) OAA + NADH ~ malate + NAD+
The fructose-1,6-diphosphate formed in reaction (1) allosterically interacts with the phosphoenolpyruvate carboxylase and activates its catalysis of reaction (2), the formation of oxaloacetate from PEP. Reaction (3) occurs in the sureounding medium, i.e., there is no necessity to bind the malate dehydrogenase to a third monoclonal antibody. The presence and/or guantity of suspect antigen is determined by correlating the reduc-tion in the absorption at 340 nm by NADH which is oxidized in reaction (3) to NAD+.
An example of an assay involving allosteric inhibi-tion employing a pair of antibodies labelled, respect-fully, with aspartate amino transferase (AST) and phos-phoenolpyruvate carboxylase can use the following re-action scheme:
AST
(lj oxaloocetate + glutamate ~ aspartate +
-ketoglutorate phosphoenolpyruvate carboxylase 30 (2) PEP + NADH ~ OAA + NAD+
^` -28-;~ :
^ ~, 12t3~40 The aspartate formed in reaction (1) inhibits the second reaction by allosterically interacting with the phosphoenolpyruvate carboxylase. This reduces the rate at which NADH is oxidized to NAD+. Therefore, the decrease in the absorption at 340 nm exhibited by NADH
can be correlated to the presence and/or quantity of antigen in the sample being assayed, a smaller decrease than occurs with a control sample indicating that antigen is present.
Those skilled in the art will appreciate that numerous other reaction pairs involving activation or inhibition of the second enzymatically catalyzed reaction can be substituted for the examples set forth above for use in a two-site assay. In another embodiment, only one of the antibody pairs is labelled with an enzyme, the second being labelled with a substance, for example, that undergoes a reaction catalyzed by the enzyme to produce a second product which can be detected and/or quantified by colorimetric, fluorimetric, luminescence, spectrophoto-metric or other technique. One such example uses a pair of monoclonal antibodies, one of which is labelled with peroxidase and the other with luminol, and takes advan-tage of the following reaction:
N~2 , per~ tl 33 dase ~~o~
+ 2~02 ---~N2 ~ 2R20 J hv ~
: ;~ ' O
luminol , ~ -29-:~
1281~0 The photon (h~) emitted by the reaction can be detected using photometric techniques and related to the presence and/or quantity of an antigen in a sample being assayed.
In yet another preferred variant of the two-site assay, the two monoclonal antibodies are, respectively, conjugated with a fluorescing chromophore and a quenching chromophore which absorbs light at the wavelength emitted by the fluorescer. The two antibodies are selected so 10 that, when they combine with the antigen for which they are specific, the two chromophores are positioned close enough to permit the light emitted by the fluorescer to be absorbed by the other chromophore. Usually, this will place them within about 100 angstroms of each other and, preferably, within about 50 angstroms of each other. The selection of suitable antibodies can be done through a screening procedure in which a mixture of fluorescent and quencher labelled monoclonal antibodies are contacted with a sample containing a known quantity 20 of antigen. Reduction of fluorescence is indicative that the two chromophores are positioned closely enough together.
Using fluorescence quenching, it is unnecessary to insolubilize either of the two antibodies. Quan-titative measurements can be made simply by measuring the decrease in maximum fluorescence, i.e., the amount of fluorescense exhibited by a control sample free of any antigen or by comparing the fluorescence of the sample with that of control samples containing a known quantity 30 of antigen. However, fluorescent-quenching chromophore ~ .
pairs can also be used in combination with the particle agglomeration technique and in the technique whereby one of the antibodies is insolubilized by being bound to a solid support such as a test tube wall or bead, since pairing of the fluorescent-quenching chromophores will occur. A decrease in fluorescence again is in-dicative of the presence or amount of antigen in the sample.
Suitable fluorescing and quenching chromophores and techniques for conjugating them with antibodies are described in United States Patent No. 4,174,384. Presently, it is preferred to use fluorescein and rhodamine as the fluorescer and quencher chromophores, respectively.
In the preceding discussion of our invention, we have described techniques of fluorescence quenching in which antibody pairs carrying the necessary chromophores are caused to bond to an antigen, if present in the sample being analyzed, in a steric arrangement which permits the quenching chromophore to absorb light emitted by the fluorescent chromophore. Quantitative deterDina-tions of the amount of antigen present are made by measuring the decrease in maximum fluorescence.
These techniques are well suited to determining the presence of antigen in a sample over a wide range of concentration. However, the small decreases in fluo-rescence which are associated with low antigen concen-tration are hard to detect and measure accura~ely. By contrast, small increases in fluorescence are relatively easy to detect and measure accurately. Accordingly, in ::
~ - 31 -:
12~l0 another aspect of our invention, we prefer to exploit the inhibition of quenching and measure increases in fluo-rescence.
To accomplish this in an assay for a particular antigen, quantities of the antigen and monoclonal anti-body to the antigen are individually labelled with one or the other of the pair of fluorescent-quencher chromo-phores. The chromophore labelled antigen and antibody are then combined to form a complex in which the fluo-rescent chromophore is positioned so that the light it emits is absorbed by the quenching chromophore. To -achieve this the antigen may be labelled with the fluo-rescer and the antibody with the quencher or vice versa.
A sample suspected of containing the antigen being assayed is then contacted with the chromophore labelled antigen and antibody. After a suitable incubation period, fluorescence is measured. If antigen is present in the assayed sample, it inhibits, at least in part, the formation of a complex between the chromophore labelled antigen and the antibody by itself forming a complex with the monoclonal antibody. To the extent this occurs, the fluorescer chromophore is no longer positioned so that the light it emits is absorbed by the quenching chromo-phore. This results in an increase in fluorescence. The increase in fluorescence can be measured and related to the concentration of antigen in the sample undergoing analysis by comparison with the fluorescence exhibited by control samples free of antigen or containing known amounts of antigen.
,i i2~316~
From the foregoing, it will be apparent that the chromophore labelled antigen:antibody complex may be a soluble one. However, it is presently preferred to employ chromophore labelled antigen and monoclonal antibody which are bound to latex or other suitable particles, for example, those listed above, of a size that will form agglomerates when the complex is formed.
Particles varying in size from about 0.2 to about 10 p are usually suitable for this purpose. When an 10 unknown sample containing the suspect antigen is con-tacted with the agglomerate forming particles of antibody and antigen, inhibition of agglomeration will occur because of sample antigen combining with particle-bound antibody. An increase in fluorescence will result, since quenching can no longer occur, which can be detected and measured to correlate with the amount of antigen in the sample by comparison with the fluoresence observed for a sample containing a known quantity of antigen.
It is also within the scope of our invention to 20 employ bound antigen and particle bound monoclonal antibody in an assay that directly measures the inhi-bition of agglomeration. In this technique, neither the antigen nor antibody is labelled. When a sample con-taining antigen is contacted with the particles, inhibi-tion of agglomeration during the incubation period will occur. This results in, at least, a partial reduction in the agglomerate formation. The inhibition is detected using nephelometry or other techniques for measuring turbidity. The decrease in turbidity can be correlated 30 to the amount of antigen in the sample.
.:-~Z~16~
The foregoing description of the invention and the examples demonstrating the application of the invention to assays for IgE are but exemplary of the various ways the invention can be utilized. That other variations will be useful will be apparent to those skilled in the art. Therefore, the present invention is to be con-sidered limited only by the appended claims.
The counts/minute for the duplicate controls and the duplicate assays of the samples containing IgE using polyclonal antibody and monoclonal antibody are shown in Tables I and II, respectively. These data were used to prepare Figures I and II in the following way. The average of the counts/minute for a control for a given incubation period was subtracted from the average of the ~; 30 counts for the corresponding IgE assay. The difference , was calculated as a percentage of the total counts/
minute of labelled antibody added to the sample and is plotted on the Y axis as the percentage of total counts/
minute of antibody bound to the solid phase. The incuba-tion time is plotted on the X axis.
A comparison of the plots shown in Figure 2 dis-playing the results of assays using monoclonal antibody with those of Figure 1 of assays using using polyclonal antibody shows that in êach kind of assay, simultaneous, 10 reverse, forward, and fast forward, the assay using monoclonal antibody was more sensitive as indicated by the higher percentage of total counts bound to the solid phase with 100 IU IgE/ml specimen. Unexpectedly, in the case of the simultaneous and reverse assays, we have found that those run with monoclonal antibody reach equilibrium more rapidly than does the corresponding assay using polyclonal antibody. Therefore, by using a monoclonal antibody in these procedures, the time for the assay can be reduced significantly beyond the time saving 20 achieved by merely eliminating a washing step. In that regard, the reverse assay with monoclonal antibody reached equilibrium in less than one hour. The same assay run with polyclonal assay did not reach eguilibrium until after 4 hours. Similarly, in the case of simulta-neous assays, the assay using monoclonal antibody reached equilibrium within 8 hours whereas the assay with poly-clonal antibody did not reach equilibrium within 24 hours. Accordingly, the present invention provides substantially more rapid and sensitive simultaneous and reverse assays than the prior art processes and elimi-nates the concern that formation of a soluble "sandwich"
complex will compete with formation of the desired insoluble complex.
In the foregoing discussion, the focus has been upon two site or sandwich assays in which one of the antibodies is insolubilized while the other is soluble in the medium analyzed. Other variations are possible. A
preferred variant employs antibodies bound to particles, 10 such as particles of latex, in a manner which results in each particle carrying a plurality of antibodies. When a quantity of particles to which a first monoclonal anti-body is bound is admixed with, for example, quantity of particles to which a second monoclonal antibody is bound, a milky suspension results. However, if a sample con-taining polyvalent antigen for which the antibodies are specific is introduced to the suspension, agglomeration or agglutination of the particles will occur to form easily detectable particle clumps.
The visual detection of agglomerate formation can be used in a screening test for presence of the antigen.
This detection can be aided by coloring the particles carrying one monoclonal antibody differently from the particle carrying the other. However, the extent of agglomeration can also be determined as a measure of the amount of antigen present in the sample. For example, the change in turbidity can be measured using standard techniques such as nephelometry.
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128~640 It is presently preferred to use latex particles to which the antibody is covalently bound using techniques well known to those skilled in the art. However, other particulate supports can be used. Among these may be mentioned silica, glass, cells, polyacrylamides, poly-methyl methacrylate and agarose. Preferably, the par-ticles vary in size between about 0.2~ to about 10~.
Visual screening, however, requires particles of at least about 1.0~.
In yet another variant, one of the antibodies is insolubilized on a bead, test tube wall or other macro-scopic solid suport, and the other is bound to small particles of latex or other suitable material. In the presence of antigen, a sandwich of the antigen between the macroscopically bound antibody and the particle bound antibody will form. By, for example, coloring the particles, formation of the sandwich can be determined visually. A fluorescent, enzymatic, radioactive or other label on the particle bound antibody can be used for 20 quantitative determinations just as in the case of using a soluble antibody described above.
In another preferred variant of the two-site assay, at least one of two different monoclonal antibodies is bound to an enzyme which catalyzes a reaction involving a substance bound to the other monoclonal antibody to produce either a detectable substance or in some other way interacts with the substance on the second antibody to permit detection of the antibody:antigen:antibody complex. Detection may be, for example, by colorimetry, 30 fluorimetry, luminescence, spectrophotometry, or the :, .
12816~0 like. It will be appreciated that, using such techniques, neither antibody needs to be insolubilized, greatly simplifying the assay.
In a presently preferred embodiment, the substance on the second antibody is also an enzyme and the assay employs the pair of enzyme labelled antibodies to cat-alyze sequential reactions, one of which produces a product required by the other. In those reactions, the two antibodies are selected so that when they bind with 10 the antigen, they are sterically positioned so that the product of the first enzymatic reaction is generated in such close proximity to the second enzyme labelled antibody, that the second reaction occurs before signif-icant diffusion of the product of the first reaction into the surrounding medium can take place.
This process can be illustrated using a pair of monoclonal antibodies, one of which is labelled with hexokinase (HK), the other with glucose-6-phosphate dehydrogenase (G-6-PDH), in the following series of 20 reactions.
HK
(1) adenosine triphosphate + glucose r (ATP) adenosine diphosphate + glucose-6-phosphate (ADP) 1~8~6~0 (2) glucose-6-phosphate + nicotinamide adenine dinucleotide (NAD+) ~ gluconolactone-6-phosphate +
dihydronicotinamide adenine dinucleotide (NADH) The assay is conducted by adding to the sample containing the suspect antigen the labelled antibodies to 10 the antigen, ATP, glucose and the coenzyme NAD+. If the antigen is present, a complex as illustrated below is formed:
- Ab(~K) Ag - Ab(G-6-PDH) The HK labelled antibody catalyzes the formation of glucose-6-phosphate in proximity to the G-6-PDH labelled antibody where it is converted to gluconolactone-6-phos-phate. The NADH formed in this reactio~ by reduction of 20 NAD+ can be detected spectrophometrically because of the strong absorption at 340 nm characteristic of a dihydronicotinamide.
The same conversion of glucose to gluconolactone-6-phosphate with formation of NADH also may occur in the medium itself catalyzed by the uncomplexed labelled antibodies, but at a much slower rate than when the two antibodies are positioned near each other in the anti-body:antigen:antibody complex. Accordingly, an increase of absorption at 340 nm compared to a control sample 30 confirms the presence of antigen in the sample. The ,, .
~2~
increase in absorption can also be corelated to the quantity of antigen in the complex.
Any other pair of suitable sequential enzymatically catalyzed reactions may be used in a two-site assay with appropriately labelled antibodies to a suspect antigen.
Among those may be mentioned the reaction of glucose catalyzed with glucose oxidase to form glucono-~-lactone and hydrogen peroxide followed by the reaction of the hydrogen peroxide with ophenylenediamine catalyzed by 10 peroxidase to produce a colored moiety. In this assay, one of the monoclonal antibodies is labelled with glucose oxidase and the other with peroxidase. The intensity of the color produced compared to a control can be corre-lated to the presence and/or amount of antigen in the sample assayed. It will be appreciated that other substances oxidizable to a colored moiety in the presence of an enzyme can be substituted for o-phenylenediamine.
Yet another suitable pair of sequential reactions using a pair of antibodies to a desired antigen labelled, 20 respectively, with NAD oxidoreductase and luciferase is the following:
NAD oxido-reductase (1) NADH + riboflavin-5'-phosphate (FMN) FMNH2 + NAD+
luciferase (2) FMNH2 + RCHO + 2 FMN* + RCOOH + H2O
RCHO is typically a straight chain aldehyde of 10 or more 30 carbon atoms.
.:
12816~0 The generation of FMN*, an excited state of FMN, is followed by the emission of a photon which can be detec-ted photometrically for correlation with a control sample to indicate the presence and/or quantity of antigen in a sample being assayed.
In another embodiment using a pair of antibodies labelled with enzymes, the product of the first enzymat-ically catalyzed reaction can be either an allosteric activator or inhibitor of the subsequent enzyme catalyzed 10 reaction. An allosteric activator, rather than being consumed in the second reaction, interacts with the enzyme to increase its affinity for a substrate or to increase the rate of conversion of the substrate to product after the enzyme-substrate complex is formed.
Allosteric inhibitors, on the other hand, have the opposite effect and reduce the enzyme's affinity for a substrate or reduce the rate of conversion of substrate to product. Allosteric inhibition may be of the compet-itive or non-competitive type.
An example of an assay involving allosteric activa-tion employing a pair of antibodies labelled, respec-tively, with phosphofructokinase and phosphoenolpyruvate uses the following reaction scheme:
phosphofructokinase (1) fructose-6-phosphate + ATP
fructose-1,6-diphosphate + ADP
12Bl~O
(2) HCO3- + phosphoenolpyruvate (PEP) phosphoenolpyruvate carboxylase - ~ oxaloacetate (OAA) malate dehydrogenase (3) OAA + NADH ~ malate + NAD+
The fructose-1,6-diphosphate formed in reaction (1) allosterically interacts with the phosphoenolpyruvate carboxylase and activates its catalysis of reaction (2), the formation of oxaloacetate from PEP. Reaction (3) occurs in the sureounding medium, i.e., there is no necessity to bind the malate dehydrogenase to a third monoclonal antibody. The presence and/or guantity of suspect antigen is determined by correlating the reduc-tion in the absorption at 340 nm by NADH which is oxidized in reaction (3) to NAD+.
An example of an assay involving allosteric inhibi-tion employing a pair of antibodies labelled, respect-fully, with aspartate amino transferase (AST) and phos-phoenolpyruvate carboxylase can use the following re-action scheme:
AST
(lj oxaloocetate + glutamate ~ aspartate +
-ketoglutorate phosphoenolpyruvate carboxylase 30 (2) PEP + NADH ~ OAA + NAD+
^` -28-;~ :
^ ~, 12t3~40 The aspartate formed in reaction (1) inhibits the second reaction by allosterically interacting with the phosphoenolpyruvate carboxylase. This reduces the rate at which NADH is oxidized to NAD+. Therefore, the decrease in the absorption at 340 nm exhibited by NADH
can be correlated to the presence and/or quantity of antigen in the sample being assayed, a smaller decrease than occurs with a control sample indicating that antigen is present.
Those skilled in the art will appreciate that numerous other reaction pairs involving activation or inhibition of the second enzymatically catalyzed reaction can be substituted for the examples set forth above for use in a two-site assay. In another embodiment, only one of the antibody pairs is labelled with an enzyme, the second being labelled with a substance, for example, that undergoes a reaction catalyzed by the enzyme to produce a second product which can be detected and/or quantified by colorimetric, fluorimetric, luminescence, spectrophoto-metric or other technique. One such example uses a pair of monoclonal antibodies, one of which is labelled with peroxidase and the other with luminol, and takes advan-tage of the following reaction:
N~2 , per~ tl 33 dase ~~o~
+ 2~02 ---~N2 ~ 2R20 J hv ~
: ;~ ' O
luminol , ~ -29-:~
1281~0 The photon (h~) emitted by the reaction can be detected using photometric techniques and related to the presence and/or quantity of an antigen in a sample being assayed.
In yet another preferred variant of the two-site assay, the two monoclonal antibodies are, respectively, conjugated with a fluorescing chromophore and a quenching chromophore which absorbs light at the wavelength emitted by the fluorescer. The two antibodies are selected so 10 that, when they combine with the antigen for which they are specific, the two chromophores are positioned close enough to permit the light emitted by the fluorescer to be absorbed by the other chromophore. Usually, this will place them within about 100 angstroms of each other and, preferably, within about 50 angstroms of each other. The selection of suitable antibodies can be done through a screening procedure in which a mixture of fluorescent and quencher labelled monoclonal antibodies are contacted with a sample containing a known quantity 20 of antigen. Reduction of fluorescence is indicative that the two chromophores are positioned closely enough together.
Using fluorescence quenching, it is unnecessary to insolubilize either of the two antibodies. Quan-titative measurements can be made simply by measuring the decrease in maximum fluorescence, i.e., the amount of fluorescense exhibited by a control sample free of any antigen or by comparing the fluorescence of the sample with that of control samples containing a known quantity 30 of antigen. However, fluorescent-quenching chromophore ~ .
pairs can also be used in combination with the particle agglomeration technique and in the technique whereby one of the antibodies is insolubilized by being bound to a solid support such as a test tube wall or bead, since pairing of the fluorescent-quenching chromophores will occur. A decrease in fluorescence again is in-dicative of the presence or amount of antigen in the sample.
Suitable fluorescing and quenching chromophores and techniques for conjugating them with antibodies are described in United States Patent No. 4,174,384. Presently, it is preferred to use fluorescein and rhodamine as the fluorescer and quencher chromophores, respectively.
In the preceding discussion of our invention, we have described techniques of fluorescence quenching in which antibody pairs carrying the necessary chromophores are caused to bond to an antigen, if present in the sample being analyzed, in a steric arrangement which permits the quenching chromophore to absorb light emitted by the fluorescent chromophore. Quantitative deterDina-tions of the amount of antigen present are made by measuring the decrease in maximum fluorescence.
These techniques are well suited to determining the presence of antigen in a sample over a wide range of concentration. However, the small decreases in fluo-rescence which are associated with low antigen concen-tration are hard to detect and measure accura~ely. By contrast, small increases in fluorescence are relatively easy to detect and measure accurately. Accordingly, in ::
~ - 31 -:
12~l0 another aspect of our invention, we prefer to exploit the inhibition of quenching and measure increases in fluo-rescence.
To accomplish this in an assay for a particular antigen, quantities of the antigen and monoclonal anti-body to the antigen are individually labelled with one or the other of the pair of fluorescent-quencher chromo-phores. The chromophore labelled antigen and antibody are then combined to form a complex in which the fluo-rescent chromophore is positioned so that the light it emits is absorbed by the quenching chromophore. To -achieve this the antigen may be labelled with the fluo-rescer and the antibody with the quencher or vice versa.
A sample suspected of containing the antigen being assayed is then contacted with the chromophore labelled antigen and antibody. After a suitable incubation period, fluorescence is measured. If antigen is present in the assayed sample, it inhibits, at least in part, the formation of a complex between the chromophore labelled antigen and the antibody by itself forming a complex with the monoclonal antibody. To the extent this occurs, the fluorescer chromophore is no longer positioned so that the light it emits is absorbed by the quenching chromo-phore. This results in an increase in fluorescence. The increase in fluorescence can be measured and related to the concentration of antigen in the sample undergoing analysis by comparison with the fluorescence exhibited by control samples free of antigen or containing known amounts of antigen.
,i i2~316~
From the foregoing, it will be apparent that the chromophore labelled antigen:antibody complex may be a soluble one. However, it is presently preferred to employ chromophore labelled antigen and monoclonal antibody which are bound to latex or other suitable particles, for example, those listed above, of a size that will form agglomerates when the complex is formed.
Particles varying in size from about 0.2 to about 10 p are usually suitable for this purpose. When an 10 unknown sample containing the suspect antigen is con-tacted with the agglomerate forming particles of antibody and antigen, inhibition of agglomeration will occur because of sample antigen combining with particle-bound antibody. An increase in fluorescence will result, since quenching can no longer occur, which can be detected and measured to correlate with the amount of antigen in the sample by comparison with the fluoresence observed for a sample containing a known quantity of antigen.
It is also within the scope of our invention to 20 employ bound antigen and particle bound monoclonal antibody in an assay that directly measures the inhi-bition of agglomeration. In this technique, neither the antigen nor antibody is labelled. When a sample con-taining antigen is contacted with the particles, inhibi-tion of agglomeration during the incubation period will occur. This results in, at least, a partial reduction in the agglomerate formation. The inhibition is detected using nephelometry or other techniques for measuring turbidity. The decrease in turbidity can be correlated 30 to the amount of antigen in the sample.
.:-~Z~16~
The foregoing description of the invention and the examples demonstrating the application of the invention to assays for IgE are but exemplary of the various ways the invention can be utilized. That other variations will be useful will be apparent to those skilled in the art. Therefore, the present invention is to be con-sidered limited only by the appended claims.
Claims (91)
1. In an immunometric assay process to determine the presence or concentration of an antigenic substance in a fluid sample comprising forming a ternary complex of the antigenic substance, a first antibody and a second antibody bound to the antigen at a different site than the first antibody by contacting the sample with said first and second antibodies, the improvement comprising employing a monoclonal antibody for each of said first and second antibodies.
2. A process according to claim 1 wherein a fluor-escent chromophore is bonded to said first antibody and a chromophore capable of absorbing light at the wavelength emitted by the fluorescent chromophore is bonded to said second antibody.
3. A process according to claim 2 wherein the sample is contacted with a solution containing the first and second antibodies to form the ternary complex and the intensity of fluorescence determined and compared to the fluorescence of a standard sample free of said antigen or containing said antigen in a known amount.
4. A process according to claim 2 wherein the first antibody is bound at the time of said determination to a solid carrier that is insoluble in the fluid sample and said second antibody is soluble in the fluid sample.
5. A process according to claim 4 wherein the fluid sample is simultaneously contacted with said first and second antibodies to form an insoluble ternary complex and the intensity of fluorescence of the ternary complex determined and compared to the fluorescence of a stan-dard sample free of said antigen or containing said antigen in a known amount.
6. A process according to claim 2 wherein the second antibody is bound at the time of said determination to a solid carrier that is insoluble in the fluid sample and said first antibody is soluble in the fluid sample.
7. A process according to claim 6 wherein the fluid sample is simultaneously contacted with said first and second antibodies to form an insoluble complex and the intensity of fluorescence of the fluid determined and compared to the fluorescence of a standard sample free of said antigen or containing said antigen in a known amount.
8. A process according to claim 4 wherein the sample is first contacted with the first antibody to form an antibody:antigen binary complex and then contacted with the second antibody to form the ternary complex and the intensity of the fluorescence of the complex or the fluid determined and compared to a standard sample free of said antigen or containing the antigen in a known amount.
9. A process according to claims 2, 3, or 4 wherein the fluorescent chromophore is fluorescein and the chromophore capable of absorbing emitted light is rhoda-mine.
10. A process according to claims 5, 6, or 7 wherein the fluorescent chromophore is fluorescein and the chromophore capable of absorbing emitted light is rhodamine.
11. A process according to claim 8 wherein the fluorescent chromophore is fluorescein and the chromo-phore capable of absorbing emitted light is rhodamine.
12. A process according to claim 1 wherein said first antibody is bound to particles insoluble in the fluid sample and said second antibody is bound to par-ticles insoluble in the fluid sample and wherein the sample is contacted with a suspension of the particles for a time sufficient to cause formation of the ternary complex whereby agglomeration of the particles bound to said first and second antibodies occurs.
13. A process according claim 12 wherein the size of the particles is in the range of from about 0.2µ to about 10µ.
14. A process according to claim 13 wherein the particles are selected from the group consisting of particles of latex, silica, glass, cells, polyacryl-amide, polymethyl methacrylate and agarose.
15. A process according to claim 14 wherein the particles are latex particles.
16. A process according to claim 12 wherein the particles binding the first antibody are of different color than the particles binding the second antibody.
17. A process according to claims 14 or 15 wherein the particles binding the first antibody are of different color than the particles binding the second antibody.
18. A process according to claims 13, 14, or 15 wherein the size of the particles is in the range of from about 1.0 to 10 µ.
19. A process according to claim 16 wherein the size of the particles is in the range of from about 1.0 to 10 µ.
20. A process according to claims 12 or 13 wherein the turbidity of the sample after formation of the ter-nary complex is determined and related to the turbidity of a control sample known to be free of the anitgen or to contain a known amount of the antigen.
21. A process according to claims 14 or 15 wherein the turbidity of the sample after formation of the ter-nary complex is determined and related to the turbidity of a control sample known to be free of the antigen or to contain a known amount of the antigen.
22. A process according to claim 12 wherein a fluorescent chromophore is bound to said first anti-body and a chromophore capable of absorbing light at the wave-length emitted by the fluorescent chromo-pore is bound to the second antibody and wherein, after said contacting, the intensity of fluorescence is determined and compared to the fluorescence of a stand-ard free of said antigen or containing said antigen in a known amount.
23. A process according to claim 14 wherein a fluorescent chromophore is bound to said first antibody and a chromophore capable of absorbing light at the wave-length emitted by the fluorescent chromophore is bound to the second antibody and wherein, after said contact-ing, the intensity of fluorescence is determined and compared to the fluorescence of a standard sample free of said antigen or containing said antigen in a known amount.
24. A process according to claim 22 wherein the fluorescent chromophore is fluorescein and the chromo-phore capable of absorbing emitted light is rhodamine.
25. A process according to claim 23 wherein the fluorescent chromophore is fluorescein and the chromo-phore capable of absorbing emitted light is rhodamine.
26. A process according to claim 1 wherein an enzyme is bound to the first antibody and a substance is bound to the second antibody whereby the enzyme interacts with the substance to permit detection of the antibody:
antigen:antibody complex.
antigen:antibody complex.
27. A process according to claim 26 wherein the substance bound to the second antibody is an enzyme.
28. A process according to claim 27 whereby the first antibody bound enzyme catalyzes a reaction which produces a product required by a reaction catalyzed by the second antibody bound enzyme.
29. A process according to claim 28 whereby the product of the reaction catalyzed by the first bound enzyme is consumed in the reaction catalyzed by the second bound enzyme.
30. A process according to claim 28 whereby the product of the reaction catalyzed by the first bound enzyme allosterically interacts with the second bound enzyme.
31. A process according to claim 30 whereby the product of the reaction catalyzed by the first bound enzyme allosterically activates the second bound enzyme.
32. A process according to claim 30 whereby the product of the reaction catalyzed by the first bound enzyme allosterically inhibits the second bound enzyme.
33. A process according to claim 28 wherein the reaction catalyzed by the second antibody bound enzyme produces a detectable product.
34. A process according to claim 30 wherein the reaction catalyzed by the second anitbody bound enzyme produces a detectable product.
35. A process according to claim 33 wherein the formation of the detectable product is detected by colorimetry, fluor-imetry, luminescence or spectrophometry.
36. A process according to claim 34, wherein the formation of the detectable product is detected by colorimetry, fluor-imetry, luminescence or spectrophotometry.
37. A process according to claim 28 wherein the reaction catalyzed by the second antibody bound enzyme consumes a detectable substance.
38. A process according to claims 30, 31 or 32 wherein the reaction catalyzed by the second antibody bound enzyme consumes a detectable substance.
39. A process according to claim 37 wherein the consumption of the detectable substance is detected by colorimetry, fluor-imetry, luminescence or spectrophotometry.
40. A process according to claim 26, wherein the substance on the second antibody undergoes a reaction catalyzed by the first antibody bound enzyme.
41. A process according to claim 40 wherein the reaction produces a substance detectable by colorimetry, fluorimetry, luminescence or spectrophotometry.
42 42. A process for the determination of the presence or concentration of an antigenic substance in a fluid, comprising the steps:
(a) contacting a sample of the fluid with a soluble first monoclonal antibody to the antigenic substance in order to form a soluble complex of the antibody and antigenic substance present in said sample, said first monoclonal antibody being labelled;
(b) contacting the soluble complex with a second monoclonal antibody bound at the time of said determination to a solid carrier, said solid carrier being insoluble in said fluid, in order to form an insoluble complex of said first monoclonal antibody, said antigenic substance and said second monoclonal antibody bound to said solid carrier;
(c) separating said solid carrier from the fluid sample and unreacted labelled antibody;
(d) measuring either the amount of labelled antibody associated with the solid carrier or the amount of unreacted labelled antibody; and (e) relating the amount of labelled antibody measured with the amount of labelled antibody measured for a control sample prepared in accordance with steps (a)-(d), said control sample being known to be free of said antigenic substance, to determine the presence of antigenic substance in said fluid sample, or relating the amount of labelled antibody measured with the amount
(a) contacting a sample of the fluid with a soluble first monoclonal antibody to the antigenic substance in order to form a soluble complex of the antibody and antigenic substance present in said sample, said first monoclonal antibody being labelled;
(b) contacting the soluble complex with a second monoclonal antibody bound at the time of said determination to a solid carrier, said solid carrier being insoluble in said fluid, in order to form an insoluble complex of said first monoclonal antibody, said antigenic substance and said second monoclonal antibody bound to said solid carrier;
(c) separating said solid carrier from the fluid sample and unreacted labelled antibody;
(d) measuring either the amount of labelled antibody associated with the solid carrier or the amount of unreacted labelled antibody; and (e) relating the amount of labelled antibody measured with the amount of labelled antibody measured for a control sample prepared in accordance with steps (a)-(d), said control sample being known to be free of said antigenic substance, to determine the presence of antigenic substance in said fluid sample, or relating the amount of labelled antibody measured with the amount
43 of labelled antibody measured for samples containing known amounts of antigenic substance prepared in accor-dance with steps (a)-(d) to determine the concentration of antigenic substance in said fluid sample.
43. A process according to claim 42 wherein said first monoclonal antibody is the product of a different cell line than said second monoclonal antibody.
43. A process according to claim 42 wherein said first monoclonal antibody is the product of a different cell line than said second monoclonal antibody.
44. A process according to claim 42 wherein said antigen has at least two identical binding sites and said first and second monoclonal antibodies are the product of the same cell line.
45. A process according to any one of claims 42, 43 or 44 wherein the first and second antibodies are selected to have an affinity for said antigen of at least about 108 litres/mole.
46. A process according to any one of claims 42, 43 or 44 wherein the first and second antibodies are selected to have an affinity for said antigen of at least 109 liters/mole.
47. A process according to claim 42 wherein said solid carrier is washed to separate the fluid sample from the carrier.
48. A process according to claim 47 wherein the solid carrier is washed with phosphate buffered saline.
49. A process according to claim 42 wherein the labelled antibody is labelled with a member selected from the group consisting of a radioactive isotope, an enzyme and a fluorogenic material and said examination is by means selected from the group consisting of radiometric means, fluorometric means and enzymatic means.
50. A process according to claim 49 wherein said label is the radioactive isotope I125.
51. A process for the determination of the presence of an antigenic substance in a fluid comprising the steps:
a) simultaneously contacting a sample of the fluid with first and second monoclonal antibodies to said antigenic substance, said first monoclonal antibody being labelled and said second monoclonal antibody being bound at the time of said determination to a solid carrier insoluble in said fluid, in order to form an insoluble complex of said first monoclonal antibody, said antigenic substance and said second monoclonal antibody;
b) separating said solid carrier from the fluid sample and unreacted labelled antibody;
c) measuring either the amount of labelled antibody associated with the solid carrier or the amount of unreacted labelled antibody; and d) relating the amount of labelled antibody measured with the amount of labelled antibody measured for a control sample prepared in accordance with steps (a)-(c), said control sample being known to be free of said antigenic substance, to determine the presence of antigenic substance in said fluid sample, or relating the amount of labelled antibody measured with the amount of labelled antibody measured for samples containing known amounts of antigenic substance prepared in accordance with steps (a)-(d) to determine the concentration of antigenic substance in said fluid sample.
a) simultaneously contacting a sample of the fluid with first and second monoclonal antibodies to said antigenic substance, said first monoclonal antibody being labelled and said second monoclonal antibody being bound at the time of said determination to a solid carrier insoluble in said fluid, in order to form an insoluble complex of said first monoclonal antibody, said antigenic substance and said second monoclonal antibody;
b) separating said solid carrier from the fluid sample and unreacted labelled antibody;
c) measuring either the amount of labelled antibody associated with the solid carrier or the amount of unreacted labelled antibody; and d) relating the amount of labelled antibody measured with the amount of labelled antibody measured for a control sample prepared in accordance with steps (a)-(c), said control sample being known to be free of said antigenic substance, to determine the presence of antigenic substance in said fluid sample, or relating the amount of labelled antibody measured with the amount of labelled antibody measured for samples containing known amounts of antigenic substance prepared in accordance with steps (a)-(d) to determine the concentration of antigenic substance in said fluid sample.
52. A process according to claim 51 wherein said first monoclonal antibody is the product of a different cell line than said second monoclonal antibody.
53. A process according to claim 51 wherein said antigen has at least two identical binding sites and said first and second monoclonal antibodies are the product of the same cell line.
54. A process according to any one of claims 51, 52 or 53 wherein the first and second antibodies are selected to have an affinity for said antigen of at least about 108 liters/mole.
55. A process according to any one of claims 51, 52 or 53 wherein the first and second antibodies are selected to have an affinity for said antigen of at least about 109 liters/mole.
56. A process according to claim 51 wherein said solid carrier is washed to separate the fluid sample from the carrier.
57. A process according to claim 56 wherein the solid carrier is washed with phosphate buffered saline.
58. A process according to claim 51 wherein the labelled antibody is labelled with a member selected from the group consisting of a radioactive isotope, an enzyme and a fluorogenic material and said examination is by means selected from the group consisting of radiometric means, fluorometric means and enzymatic means.
59. A process according to claim 58 wherein said label is the radioactive isotope I125.
60. In an immunometric assay for the determination of the presence or concentration of an antigenic substance in a sample of a fluid comprising forming a ternary complex to a first labelled antibody, said antigenic substance, and a second antibody, said second antibody being bound at the time of said determination to a carrier insoluble in said fluid, the improvement comprising employing a monoclonal antibody for each of said labelled antibody and said antibody bound to a solid carrier.
61. A process according to claim 60 wherein the fluid sample is first contacted with the second antibody to form a binary complex of the antigenic substance and said second antibody insoluble in the fluid and then contacted with said first labelled antibody to form the ternary complex.
62. A process according to claim 60 wherein the fluid sample is first contacted with the second antibody to form a binary complex of the antigenic substance and said second antibody insoluble in the fluid, the sample separated from the solid carrier and the solid carrier contacted with a solution of said first labelled antibody to form said ternary complex.
63. A process according to claim 60 wherein said first monoclonal antibody is the product of a different cell line than said second monoclonal antibody.
64. A process according to claim 61 wherein said first monoclonal antibody is the product of a different cell line than said second monoclonal antibody.
65. A process according to claim 62 wherein said first monoclonal antibody is the product of a different cell line than said second monoclonal antibody.
66. A process according to claim 60 wherein said antigen has at least two identical binding sites and said first and second monoclonal antibodies are the product of the same cell line.
67. A process according to claim 61 wherein said antigen has at least two identical binding sites and said first and second monoclonal antibodies are the product of the same cell line.
68. A process according to claim 62 wherein said antigen has at least two identical binding sites and said first and second monoclonal antibodies are the product of the same cell line.
69. A process according to any one of claims 60, 61, 62, 63, 64, 65, 66, 67 or 68, wherein the first and second antibodies are selected to have an affinity for said antigen of at least about 108 liters/mole.
70. A process according to any one of claims 60, 61, 62, 63, 64, 65, 66, 67 or 68 wherein the first and second antibodies are selected to have an affinity for said antigen at least about 109 liters/mole.
71. A process according to claim 62 wherein said solid carrier is washed to separate the fluid sample from the carrier.
72. A process according to claim 71 wherein the solid carrier is washed with phosphate buffered saline.
73. A process according to claim 60 wherein the labelled antibody is labelled with a member selected from the group consisting of a radioactive isotope, an enzyme and a fluorogenic material.
74. A process according to claim 73 wherein said label is the radioactive isotope I125.
75. In an immunometric assay kit for the determination of the presence or concentration of an antigenic substance in a sample of a fluid comprising reagents for forming a ternary complex to a first labelled antibody, said antigenic substance, and a second antibody, said second antibody being bound at the time of said determination to a carrier insoluble in said fluid, the improvement comprising employing a monoclonal antibody for each of said labelled antibody and said antibody bound to a solid carrier.
76. A kit according to claim 75 wherein said first monoclonal antibody is the product of a different cell line than said second monoclonal antibody.
77. A kit according to claim 75 wherein said antigen has at least two identical binding sites and said first and second monoclonal antibodies are the product of the same cell line.
78. A kit according to any one of claims 75, 76 or 77 wherein the first and second antibodies are selected to have an affinity for said antigen of at least about 108 liters/mole.
79. A kit according to any one of claims 75, 76 or 77 wherein the first and second antibodies are selected to have an affinity for said antigen of at least about 109 liters/mole.
80. A kit according to claim 75 wherein the labelled antibody is labelled with a member selected from the group consisting of a radioactive isotope, an enzyme and a fluorogenic material.
81. A kit according to claim 80 wherein said label is the radioactive isotope I125.
82. A reagent for immunological assay of antigens based on the sandwich method, characterized in that it comprises insolubilized monoclonal antibody and labelled monoclonal antibody, said monoclonal antibodies respectively being capable of distinguishing and binding to different antigen determinants of an antigen to be assayed.
83. An improved sandwich method for immunological assay of antigens wherein the improvement resides in the fact that insolubilized antibody and labelled antibody react simultaneously with an antigen to be assayed, said insolubilized antibody and labelled antibody comprising monoclonal antibodies capable of distinguishing and respectively binding to different antigen determinants of said antigen.
84. An improved sandwich method for immunological assay of antigens wherein the improvement resides in the fact that insolubilised antibody and labelled antibody react simultaneously or in several incubation steps with an antigen to be assayed, said insolubilized antibody and labelled antibody comprising monoclonal antibodies capable of distinguishing and respectively binding to different antigen determinants of said antigen.
85. A mixture of monoclonal antibodies useful in an enhanced sensitivity assay for detecting an antigen in a sample which comprises an effective assaying amount of each of at least two monoclonal antibodies which bind to different antigenic sites on the antigen and which are capable under appropriate conditions of forming a stable complex which includes the antigen and all of the monoclonal antibodies.
86. A reagent according to claim 82 wherein said monoclonal antibodies are selected to have an affinity for said antigen of at least about 108 liters/mole.
87. A reagent according to claim 82 wherein said monoclonal antibodies are selected to have an affinity for said antigen of at least about 109 liters/mole.
88. The method according to claim 83 or 84 wherein said monoclonal antibodies are selected to have an affinity for said antigen of at least about 108 liters/mole.
89. The method according to claim 83 or 84 wherein said monoclonal antibodies are selected to have an affinity for said antigen of at least about 109 liters/mole.
90. A mixture according to claim 85 wherein each of said monoclonal antibodies is selected to have an affinity for said antigen of at least about 108 liters/mole.
91. A mixture according to claim 85 wherein each of said monoclonal antibodies is selected to have an affinity for said antigen of at least about 109 liters/mole.
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CA000473725A CA1195926A (en) | 1980-08-04 | 1985-02-07 | Immunometric and inhibition assays using monoclonal antibodies |
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US3654090A (en) * | 1968-09-24 | 1972-04-04 | Organon | Method for the determination of antigens and antibodies |
NL154600B (en) * | 1971-02-10 | 1977-09-15 | Organon Nv | METHOD FOR THE DETERMINATION AND DETERMINATION OF SPECIFIC BINDING PROTEINS AND THEIR CORRESPONDING BINDABLE SUBSTANCES. |
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US4016043A (en) * | 1975-09-04 | 1977-04-05 | Akzona Incorporated | Enzymatic immunological method for the determination of antigens and antibodies |
JPS5347518A (en) * | 1976-10-07 | 1978-04-28 | Mochida Pharm Co Ltd | Immunologically measuring method |
US4098876A (en) * | 1976-10-26 | 1978-07-04 | Corning Glass Works | Reverse sandwich immunoassay |
NL185309C (en) * | 1980-07-28 | 1990-03-01 | Akzo Nv | METHOD FOR DETERMINING ANTIGENS USING TWO OR MORE MONOCLONAL ANTIBODIES AND IMMUNE REAGENTS. |
US4376110A (en) * | 1980-08-04 | 1983-03-08 | Hybritech, Incorporated | Immunometric assays using monoclonal antibodies |
-
1980
- 1980-08-04 US US06/175,133 patent/US4376110A/en not_active Expired - Lifetime
-
1981
- 1981-07-29 IT IT8123231A patent/IT1225944B/en active
- 1981-07-31 CA CA000382964A patent/CA1281640C/en not_active Expired - Lifetime
- 1981-08-04 BE BE0/205580A patent/BE889855A/en not_active IP Right Cessation
- 1981-08-04 JP JP56122347A patent/JPS57118159A/en active Granted
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1991
- 1991-12-09 JP JP3324583A patent/JPH0587816A/en active Pending
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JPH0587816A (en) | 1993-04-06 |
IT8123231A0 (en) | 1981-07-29 |
JPS57118159A (en) | 1982-07-22 |
BE889855A (en) | 1982-02-04 |
JPH0421818B2 (en) | 1992-04-14 |
IT1225944B (en) | 1990-12-10 |
US4376110A (en) | 1983-03-08 |
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