AU630084B2 - The use of monoclonal antibodies (mabs) as procedure control for immunometric assays - Google Patents
The use of monoclonal antibodies (mabs) as procedure control for immunometric assays Download PDFInfo
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- AU630084B2 AU630084B2 AU30242/89A AU3024289A AU630084B2 AU 630084 B2 AU630084 B2 AU 630084B2 AU 30242/89 A AU30242/89 A AU 30242/89A AU 3024289 A AU3024289 A AU 3024289A AU 630084 B2 AU630084 B2 AU 630084B2
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- 238000013198 immunometric assay Methods 0.000 title description 2
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/10—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from RNA viruses
- C07K16/1081—Togaviridae, e.g. flavivirus, rubella virus, hog cholera virus
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/081—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from DNA viruses
- C07K16/085—Herpetoviridae, e.g. pseudorabies virus, Epstein-Barr virus
- C07K16/088—Varicella-zoster virus
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/08—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses
- C07K16/081—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from viruses from DNA viruses
- C07K16/085—Herpetoviridae, e.g. pseudorabies virus, Epstein-Barr virus
- C07K16/089—Cytomegalovirus
Description
1~ COMMONWEALTH OF AUSTRALIA PATENTS ACT 1952-69 COMPLETE SPECIFICATION
(ORIGINAL)
Class Application Number: Lodged; Form I t. Class Ca~rplete Specification Lodged: Accepted: Published: Prrlty: Peated Art: Name of Applicant: Address of Applicant: Actual Inventor; Address for Service BEHRINGWERKE AKTIENGESELLSCHAFT D-3550 Marburg, Federal Republic of Germany HANS-DETLEF DOPATKA E DWD. WATERS SONS, 50 QUEEN STREET, MELBOURNE, AUSTRALIA, 3000.
Complete Specification for the invention entitled: THE USE OF MONOCLONAL ANTIBODIES (mAbs) AS PROCEDURE CONTROL FOR IMMUNQMETRIC ASSAYS The following statement Is a full description of this Invention, Including the best map'nod of performing it known to '*US ppa. tein ppa. Bu lak- BEHRINGWERKE AG HOE 88/B 001 Ma 661 Dr.LP/St Description The use of monoclonal antibodies (mAbs) as procedure control for immunometric assays The invention relates to the use of monoclonaL antibodies (mAbs) of suitable specificity as procedure control in immunometric assaysAwhich are aimed at detecting specific antibodies, for example in enzyme-linked immunosorbent assays (ELISAs), radioimmunoassays (RIAs), fluoresce're immunoassays (FIAs), luminescence immunoassays LIAs) or similar assay methods. The invention is described in ELISAs herein- 15 after, because ELISAs currently have the widest range of application, but this is not to be understood to be a restriction to this assay method.
The requirements of national approving authorities or, 20 in advance of these, opinion-forming committees applying to an "ideal" assay control in ELISAs, which have most recently been summarized for the Federal Republic of Germany in "Richtlinien fur die DurchfUhrung von Enzym- Immuno-Assays bzw. Enzym-Liganden-Assays" (Guidelines for carrying out enzyme immunoassays or enzyme-ligand assays), Lab. med. 10, 391-392 (1986), are continuously increasing in scope. The following guidelines can be fulfilled only with difficulty by manufacturers of diagnostic aids using the assay controls which are based on polyclonal antibodies and are customary at present: Statement of criteria for checking the utility of the reagents by the user by means of a statement of the maximum permissible deviations in the measured results (range of variation) 'elative to the different sections of the standard plot.
In assays with a yes/no result: Statement of the measurement range (range of variation) in which the controls I i L 2 which are used must lie if the reagents react properly.
Statement of the maximum permissible standard deviations or relative standard deviations (coefficients of variation) in the various regions of the standard plot.
In assays with a yes/no result: Statements of the results of studies on the analytical sensitivity and diagnostic sensitivity of the assay. Furthermore statements of when the result is to be regarded as "positive with certainty", as "negative with certainty" or as "doubtful".
There is now a desire by the user to obtain quantitative results, even in ELISAs for detecting specific antibodies, 15 from a single sample from a patient, whereby the "control portion" within an assay system which has undergone overall improvement must likewise be improved.
Those skilled in the art were hitherto of the opinion 20 that the control necessary in the abovementioned assays can best be achieved by "control substances" which are as similar as possible to the body fluids which are to be assayed as a rule sera. These "control substances" are prepared from high-titer antisera from human donors or 25 donor animals, and contain a mixture of polyclonal anti- *6 *6 S' bodies and thus are equivalent to the samples to be assayed. In addition, it has been regarded as an advantage to use at the same time therewith a natural "matrix" as part of this control in order in this way also to detect matrix effects however varying and poorly reproducible in the samples by the control.
The mAbs hitherto available, mainly of murine origin, are used in diagnosis either for detecting antigens or for immobilizing antigenic reagent on the solid phase. We have found that mAbs of human, porcine, bovine etc. origin with suitable specificity can be used as control in the assays mentioned in the introduction, because with singlepoint measurements the control is improved therewith and, i -J 3 in particular, the following advantages are connected therewith.
1. Hitherto, suitable 3ssay controls have been prepared from previously assayed and selected individual single blood donations (plasma donations). This results in an upper limit on the batch size, with affinities differing from batch to batch and resulting in each case as the total of the various individual affinities of the "cocktail" of polyclonal antibodies present in this donation. These different affinities of the polyclonal controls result in different assay values (Lehtonen, and Eerola, E.
(1982), J. Immunol. Meth. 54, 233-240) which may impair the control function. The use of suitable mAbs permits 15 the preparation of controls in a batch size which is o*I theoretically unlimited, with the same affinity from batch to batch, which additionally drastically reduces the elaboration of the manufacturer's testing.
20 2. As a rule, in antibody-detecting ELISAs, the solid phase is coated with a mixture, which changes from batch to batch, of various antigens, for example of a virus.
Controls which are based on polyclonal antibodies may then react very differently to a changing composition of the antigen mix on the solid phase. Controls which are I based on mAbs do not show these variations as long as the I antigens which are required for the assay procedure are present in sufficient quantity and, furthermore, the controls reliably demonstrate the absence thereof in the solid phase.
3. Even in ELISAs using defined coating antigens prepared by genetic manipulation, it is possible for the use of controls which are based on polyclonal antibodies to cause problems. Thus, for example, it is known, when detecting antibodies against human cytomegalovirus
(HCMV),
that the neutralizing antibodies in a test sample are directed against the so-called gp 58 portion of the antigen.
However, all the assay controls which are based on I r I 4 polyclonal antibodies and are currently known for detecting HCMV antibodies contain antibodies of which only a portion, which changes from batch to batch, reacts with gp 58, with corresponding impairment of tbh control function.
4. It is advantageous if the immunoLogically reactive component of the control is not exposed to the different interfering substances (matrices), which are possible f Om test sample to test sample, since only this makes the artigen-antibody reaction, which is to be controlled, representative. This is a serious problem which, for example, the WHO has attempted to counter in another way by creating a scarcely practicable "matrix standard" 15 (WHO/BS/85.1462, Geneva, November 12-18, 1985).
o In the current commercial ELISAs, the above requirement can only partially be complied with by a particularly high predilution of high-titer single donations which 20 have been troublesome 'o find. Controls which are based *a 0 on mAbs can be prepared with a define'd matrix.
5. In the case of biological specimens, any risk of infection, for example by HIV or hepatitis viruses, must be ruled out. This is not guaranteed in every case with the blood donations which are customarily used to prepare the assay controls, despite the existence of test assays.
There may, especially in the early phase of HIV infection, be false-negative findings with these assays, especially in the case of isolated HIV-2 infections or if certain rheumatoid factors are contained in the test sample.
The listed requirements are met in their totality only by mAbs, because they can be prepared with specific properties in a defined manner. These mAbs can also be very readily established as a substandard of a atioaz or internctional antibody standard which exists where appropriate.
I- rr~ 5 E x a ip les Human monoclonal antibodies (hmAbs) of differing virus specificity are tested hereinafter in the various antibodydetecting Enzygnost assays (Behringwerke AG) for use as controls in human diagnosis. Corresponding, suitable porcine mAbs or bovine mAbs can be used in veterinary diagnostic assays, for example Enzygnost Aujeszky, Enzygnost bovine leukosis. Use in the relevant assay systems is furthermore possible by a choice of the immunoglobulin class (for example IgG, IgM, IgA) or subclass (IgGI or IgG 2 I. Isolation of suitable hmAbs against rubella virus so's Blood from a seropositive donor is centrifuged on a Ficoll-Paque
R
(Deutsche Pharmacia GmbH) density gradient, and the blood Lymphocytes are isolated.
The cells are diluted with RPMI 1640 10 FCS (from 20 Flow) to a cell concentration of 2x10 /ml.
The B lymphocytes are immortalized with a culture supernatant containing Epstein-Barr virus (EBV). The T cells are inhibited by addition of 0.5 Ug/mni cyclosporin A.
After the transformed cells have grown, a culture supernatant in each well is tested in the Enzygnost rubella for the presence of specific antibodies. Where the finding is positive, the cells are fused with a human tumor B-cell line (for example GM 1500 6TG OUA+ described in JAMES, BELL, G.Th. J. Imm. Meth. 100 (1987), page 40) or a mouse myeloma cell (for example SP2 described in PINTUS, RANSOM, J. EVANS, J. Imm. Meth. 61, 1983), 195-200).
The resulting hybrids are in turn assayed with an ELISA c~~c for antibody A for antibody
I
6 The positive cells are subsequently cloned (limiting dilution 1 cell/well). Several reclonings (minimum 2x) result in a stable human IgG-producing cell which can be used as source for the desired human mAbs (hmAbs).
The antigen against which the antibodies are directed i is determined by Western blotting. It emerged from these tests that the antibodies of the hybridoma 7H4 i 10 are directed against the large coat protein (El) of Srubella virus.
2. Isolation of suitable hmAbs (IgG) against varicella zoster virus (VZV) and other antigens 00. hmAbs against varicella zoster virus are obtained in a manner identical to that of Example 1, using the Enzygnost varicella/zoster for screening and testing the specificity. hmAbs against other desired antigens 20 can be obtained in an appropriate modification.
3. Isolation of mAbs of other species a) Porcine mAbs can be prepared as described by F. Buchegger et al. (1987) J. of the Nat. Canc. Inst.
79, 337-342, using the relevant antigens, for example Aujeszky virus.
b) Bovine mAbs can be prepared, with appropriate modification, as described in or by ANDERSON D.V. et al., Vet. Immunol. Immunopath. 15 (1987), 223-237, and TUCKER, EM. et al., Anim. Genet. 18 (1987), 29-40 and RAYBOULD, T. et al., AM.J.Vet.Res. 46 (1985), 426-427.
c) Murine mAbs can be produced as described by Kbhler and Milstein K'hler and C. Milstein (1975) Nature 256, 495).
II II I 4. Use of the ant the Enzygnost 7 i-rubella hmAb 7H4 as positive control in rubella.
S
S
0 555* *e S.
S. S *5
S
55 Enzygnost rubella (Behringwerke AG) is a commercially available sandwich ELISA for detecting rubella-specific antibodies in human sera. This entails purified rubella virus antigens being bound to the wells of a microtiter plate (MTP) and, after incubation where appropriate, bound specific antibodies being detected in the serum sample by an anti-human IgG or IgM enzyme conjugate (in this case: anti-human IgG conjugate). The abovementioned hmAb control is used like a patient's sample and, in serial dilutions by a factor of 4 each time, yields a final titer of 1:30720.
The results are compiled in Tab. 1, with the middle column in each case being the difference of the absorption in the antigen column 3, minus the absorption in the control antigen column 4, 6, 12).
The extinctions in response to a control antigen coating in the even-numbered columns 2, 4 12, with the control antigen being obtained by analogous purification of cell material not infected with r ella virus) are, in contrast to a polyclonal control, all 0.013 OD 40 5 and thus lower by a factor of 5 to When this hmAb control is used in other Enzygnost(R assays such as EnzygnostR) cytomegalovirus, VZV, anti-HSV, measles or parotitis, the titer is 1:40, i.e. the cross-reactivity is virtually zero. Polyclonal controls as a rule harbor antibodies against many pathogens, which restricts their use.
S. S
S
S
55 7
S.
Sr S; S
S
*SS S S C aS* S S S a~ *S Table 1 zrjst Th cytomegalo- varicela! virus zoster measles FBM.rst parotitis rubella anti-HSV Series1 SeriesZeries3 Series seri'5 series 6series 7 Series8Series 9 Seriesl0seriesil SeriesJ2 .009 =oo .001 1.619 1.6c6 0.13 .1 oo5 .016 .a .006 .02 =0.0 .004 .001 1.543 1.535 .008 .013 .O7 .006 .0(9 .0(6 .003 =0.0 =0.0 .004 =0.0 1.36 .32 .014 .012 .0X9 .003 .D4 =0.0 =00 =0.0 .OUT .004 .03 =0.0 M4 1.01 .0314 oo o0 o0 .0014 .0035 =0.0 =0.0 0 =0.0 .001 =0.0 .002 .435 .428 .0CY .06 .002 .0014 =o.o =0.0 .003 .001 .002 .005 .001 .0oc0 .152 .144 .OOB .0(8 .001 .0C17 .0(B .001 .017 .003 .045 .039 MG =0O.0 =0.0 .002 =0.0 =0.0 =0.0 =o.0 .016 m, .OOg =o.o .003 .002 .001 A 1:10 1:3U204 1:140 i:: 1:4o- I i 9 Use of the anti-VZV hmAb 6/870204 in the Enzygnost varicella/zoster The use of the abovementioned hmAb 6/870204 in the Enzygnost varicella/zoster is in analogy to Example 4.
The results are compiled in Tab. 2.
Thus the anti-human IgG conjugate which is customarily used demonstrates that these hmAbs are reLiable.
Furthermore, the affinity of the hmAbs bound to the solid phase is sufficient to withstand the repeated washing steps in the ELISA procedure.
6 S*
S
i 0
*S
5* 1'* i r r r r r r C
S
S S S S S S S S 5 *5 S S L S *S S S S,
SS
Table 2 alwmt B-Vr~t cytoregalo- varicella/ virus zoster rubella measles parotitis anti-flSV Series I Series 2 Series3 Series 4 Series5 series 6 series 7 Series 8 .117 .034 .083 2.156 2.067 .089 .106 ON .002 .120 .023 .o .082 .016 .066 2.419 3.351 .069 -OTT .c06 .o .076 =0.0 .088 .070 .09 .061 2.317 2.256 .061 .069 X04 .06 .061 =0.0 .078 .065 .0)3 .062 2.022 1.960 .062 .069 .003 .066 .062 .081 .964 .003 .061 1.2G9 1.209 .069 .069 .Ci 65 o.089 =0.0 o.09 .063 05 -058 -53 .4T7 .061 .068 .0 .065 .06) =0.0 .067 .061 .005 .056 .199 .139 060 .065 .02 .063 .069 =0.0 .122 A6 =o.o o2 .o97 .o3T .o6o .067 .005 02 -059 .1143 Series9 Series 10 Seriesil series 12 .014 =0.0 .073 .0148 .o7 .081 .070 =0.0 .082 .0140 =0.0 .068 .065 =0.0 .081 .057 .001 .056 .061 =0.0 .068 .057 =0.0 X57 .061 =0.0 .070 .o7 =0.0 o097 .066 =0.0 .070 .053 .093 -055 .070 .001 .09 .061 =0.0 .062 .067 =0O.O .068 .061 =0.0 .065 Tiber 4 1:40 1(1 (:110 1: 4 -u
Claims (2)
- 8. An assay kitlomprlsng solid phase carriers coated with antigen specific for the S antibody to be detected and one or more labeled monoclonal antibodies (mAbs) for the Er,- i 12 purpose of use as a procedure control in determriing a value for said specific antibody bound to said antigen.
- 9. The assay kit as claimed in claim 8 wherein mAb or mAbs are human, porcine or bovine mAbs. DATEDf this 19th day of December, 1991. BEHRINGWERKE AKTIFENGESELI-SOHAFT7 WATERMARK PATENT TRADEMARK ATTORNEYS THE ATRIUM 290 BURWOQD ROAD HIAWTHORN VIOTORIA 3122 AUSTRALIA AU3024289.WPC ge a 4 40* *4 a A a a a a. r a 4 A a. a. a a a a 4.~a*a 4 a a *4 .4 I. a 4. a- a a L'' d
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE3805716A DE3805716A1 (en) | 1988-02-24 | 1988-02-24 | USE OF MONOCLONAL ANTIBODIES (MAK) AS A PERFORMANCE CONTROL FOR IMMUNOMETRIC TESTS |
DE3805716 | 1988-02-24 |
Publications (2)
Publication Number | Publication Date |
---|---|
AU3024289A AU3024289A (en) | 1989-08-24 |
AU630084B2 true AU630084B2 (en) | 1992-10-22 |
Family
ID=6348030
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
AU30242/89A Ceased AU630084B2 (en) | 1988-02-24 | 1989-02-23 | The use of monoclonal antibodies (mabs) as procedure control for immunometric assays |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0330902A3 (en) |
JP (1) | JPH0210161A (en) |
AU (1) | AU630084B2 (en) |
DE (1) | DE3805716A1 (en) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
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CN1924579A (en) * | 2005-07-04 | 2007-03-07 | 上海富纯中南生物技术有限公司 | Cross-linked composite used as standard diagnosing reagent replacing positive serum and method for use as standard reagent |
CN105548537A (en) * | 2015-12-11 | 2016-05-04 | 郑州安图生物工程股份有限公司 | Rubella virus IgG antibody affinity detection kit |
Citations (1)
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US8600994B1 (en) * | 2010-09-02 | 2013-12-03 | Teradata Us, Inc. | Performing an outer join between a small table and a large table |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4613576A (en) * | 1983-03-09 | 1986-09-23 | Sloan-Kettering Institute For Cancer Research | Human monoclonal antibodies to cancer cells |
GB8419458D0 (en) * | 1984-07-31 | 1984-09-05 | Axon Healthcare Ltd | Antibody detection |
-
1988
- 1988-02-24 DE DE3805716A patent/DE3805716A1/en not_active Withdrawn
-
1989
- 1989-02-14 EP EP19890102504 patent/EP0330902A3/en not_active Withdrawn
- 1989-02-23 JP JP1041962A patent/JPH0210161A/en active Pending
- 1989-02-23 AU AU30242/89A patent/AU630084B2/en not_active Ceased
Patent Citations (1)
Publication number | Priority date | Publication date | Assignee | Title |
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US8600994B1 (en) * | 2010-09-02 | 2013-12-03 | Teradata Us, Inc. | Performing an outer join between a small table and a large table |
Also Published As
Publication number | Publication date |
---|---|
JPH0210161A (en) | 1990-01-12 |
AU3024289A (en) | 1989-08-24 |
DE3805716A1 (en) | 1989-09-07 |
EP0330902A3 (en) | 1990-10-24 |
EP0330902A2 (en) | 1989-09-06 |
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