EP0418283A1 - Antikörper - Google Patents

Antikörper

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Publication number
EP0418283A1
EP0418283A1 EP89906389A EP89906389A EP0418283A1 EP 0418283 A1 EP0418283 A1 EP 0418283A1 EP 89906389 A EP89906389 A EP 89906389A EP 89906389 A EP89906389 A EP 89906389A EP 0418283 A1 EP0418283 A1 EP 0418283A1
Authority
EP
European Patent Office
Prior art keywords
antibodies
antigen
antibody
cells
animal
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Withdrawn
Application number
EP89906389A
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English (en)
French (fr)
Inventor
Agamemnon Antoniou Epenetos
Nigel Stephen Courtenay-Luck
Gregory Byron Sivolapenko
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Cancer Research Horizons Ltd
Original Assignee
Imperial Cancer Research Technology Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Imperial Cancer Research Technology Ltd filed Critical Imperial Cancer Research Technology Ltd
Publication of EP0418283A1 publication Critical patent/EP0418283A1/de
Withdrawn legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/42—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins
    • C07K16/4208—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig
    • C07K16/4241—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig
    • C07K16/4258—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig against anti-receptor Ig
    • C07K16/4266—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against immunoglobulins against an idiotypic determinant on Ig against anti-human or anti-animal Ig against anti-receptor Ig against anti-tumor receptor Ig
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies

Definitions

  • the present invention relates to anti-idiotype antibodies, to a process for their production and to their use as therapeutic agents and diagnostic reagents.
  • an antibody When an antibody is administered to an animal it is possible that it will act as an immunogen and elicit an immune response such that the animal produces its own antibodies which recognise sites on the original antibody. Some of these will recognise the antigen binding site of the original antibody (i.e. the paratope) whilst others recognise sites elsewhere on the variable region (i.e, idiotopes) .
  • the anti-paratopic antibodies have a binding site which fits the paratope of the original binding site and which.must therefore have the same or very similar structure to the original antigen. These antibodies are know as anti-idiotype antibodies and are regarded as bearing an "internal image" of the antigen.
  • Anti-idiotype antibodies can be isolated and administered to other animals in which they will also act as an immunogen and elicit production of
  • anti-Id 2 which recognise the paratope of the anti-Id1 and thus contain an internal image of the original
  • anti-Id formation has only been achieved experimentally by the process of isolating the antibody, using it as an antigen, isolating the anti-Id and using that in turn as an antigen.
  • MA-Id therapeutic agents and diagnostic reagents
  • the present invention provides a
  • the animal may be a human or non-human mammal though ethical considerations may limit the use of humans in this process.
  • non-human mammals conventional laboratory rodents, "especially rats and mice, and primates will be preferred.
  • MAb's may be readily available for instance from commercial sources or by culturing deposited hybridomas.
  • Inoculation is by any of the usual routes such as intraperitoneal, intravascular , intramuscular or subcutaneous injection and the quantity of the monoclonal antibody (hereafter "MAb") inoculated will be selected depending upon the immunogenicity of the MAb. Typical quantities are from 1 to lOug for mice and about 30mg for humans. In order to elicit satisfactory antibody production the inoculation may be repeated once or more at intervals of a few days to a few weeks. The skilled person is aware of the standard schedules for such inoculations.
  • MAb monoclonal antibody
  • Antibodies may be recovered by conventional separation techniques. Since the inoculated MAb will rapidly be cleared from the body fluids, any antibody found in the body fluids after a suitable interval which is specific for the antigen against which the MAb is directed. will necessarily be an anti-Id2. Fragments of anti-Id2 may be produced by conventional methods. Preferred fragments are F(ab' )- fragments.
  • the invention also provides a process for producing cells capable of producing anti-Id against an antigen comprising inoculating an animal with MAb against an antigen and recovering cells from a tissue or body fluid of the animal which secrete antibody against the antigen.
  • the cells may be recovered for instance from the peritoneal cavity, the spleen or the blood, splenocytes and peripheral blood lymphocytes being particularly convenient.
  • the invention alternat ively pr ov ides a process
  • the invention further provides a process for
  • Immortalisation may be effected by for instance treatment with Epstein-Barr virus (EBV) or by fusion with an immortal cell such as a tumour cell especially a myeloma cell.
  • EBV Epstein-Barr virus
  • an immortal cell such as a tumour cell especially a myeloma cell.
  • the invention also provides (i) immortal cell lines capable of secreting anti-Id 2 against an antigen and
  • the process of the present invention is particularly advantageous in that it permits the binding site ( paratope) of a first MAb to be copied and produced on a large scale in the form of a second MAb .
  • the second MAb may be of a different species to the first ( useful for instance in avoiding spec ies - spec ies interactions and overcoming problems of instabil ity in the hybr idoma cell wh ich secretes the or ig inal MAb) and/or it may be of a d ifferent immunoglobul in class or subclass from that of the f ir st MAb (useful especially with human antibod ies where to date most MAb * s are IgM yet IgG is normally requ ired for therapy and diagnosis) .
  • the process also repre sents a considerable saving of time and labour over previous attempts to generate anti-Id 2 by iterative immunisation, recovery and purification steps.
  • the processes therefore involve either the use of MAb derived from a species different from the inoculated animal or the
  • MA-Id especially MA-Id . and fragments thereof , may be used in any conven tional appl ication in therapy - for instance for pass ive immunisation , or for tumour destr uction using an i munotoxin and in any conventional diagnostic application s uch as Rad io I munoassay , Enzyme Linked Immuno- sorbent
  • the invent ion therefore provides 2 a) Anti-Id for use in a method of therapy or d iagnos is practised on the human or animal body .
  • a method of therapy or diagnosis comprising administering to a human or non-human animal an effective, non-toxic amount of anti-Id 2 or cells capable of secreting
  • a diagnostic assay procedure comprising contacting a sample suspected to contain an immunogen with anti-Id 2 .
  • Figure 1 binding of patient's serum antibodies to the administered murine Mab (HMFGl) and a control antibody of the same isotype, but idiotypically unrelated (1141), in an ELISA, after a single therapeutic administration of radiolabeled murine Mab.
  • Figure 2_ shows typical comparative binding of patient's serum antibodies, after 2 or more therapeutic administrations of radiolabeled murine Mabs, to the administered (HMFGl) and control (1141) murine monoclonal antibodies coated onto 96-well microtiter plates.
  • the anti-idiotypic component is obtained by subtraction of binding results for 1141 from HMFGl.
  • Nen-specific binding to antigen-free wells was evaluated by using the ELISA coating buffer (E.C.B.) alone.
  • Figure 3 ⁇ shows the results obtained by comparing the binding of serum antibodies from patient 11 to F(ab') 2 fragments of the administered (HMFGl) and control (1141) monoclonal antibodies with the anti—idiotypic response being obtained by subtraction. Essentially identical results were obtained when sera from other patients who had received two or more therapeutic administrations of radiolabeled murine Mabs.
  • Figure _4 shows the percentage that the administered murine monoclonal antibody HMFGl (10y_/g/ml) is inhibited by patient 15's pre and post 3rd therapy serum (1/10 dilution).
  • Figure 5_ shows the inhibition of the administered murine monoclonal antibody binding to its antigen by human antibodies present in the serum of patient 15 prior to (pre) and post four therapeutic adminstrations of radiolabeled murine monoclonal antibodies (PI, P2, P3 and P4).
  • PI, P2, P3 and P4 radiolabeled murine monoclonal antibodies
  • Figure 6 ⁇ shows the binding of the administered murine monoclonal antibody, HMFGl at lO g/ml (A) to its antigen (MFG) and the inhibition of this binding by patient 15's pre-therapy serum (B) post 3rd therapy serum (C) post 3rd therapy Ig devoid serum (D) and post 3rd therapy serum Ig fraction, after protein-A purification of post-third therapy serum.
  • Figure 1_ shows the binding of patient 15's (Table 1) serum antibodies to the tumor associated antigen (that used to raise the administered murine Mab) prior to (- ⁇ 7 " )-) and post 3rd therapy, (- ⁇ >-)- Also shown is the effect on the anti-tumor response of removing serum antibodies reacting with the administered murine Mab (- ⁇ —) including the anti-id' antibodies.
  • Figure 8_ shows the results of autoantibody screening by immunofluorescence.
  • Fig. 8A shows that no pre-existing autoreactive antibodies were detectable in this present patient (patient 15) when assayed on fresh frozen sections of rat liver. No other patients' pre-therapy serum gave positive staining (Table 1).
  • patient 15's serum contained high levels of antibodies directed against connective tissue components of liver (8B), kidney glomerulus (8D) and diaphragm (8E). This generation of autoantibodies was no longer detectable after a fourth administration, as shown in Figure 8C, indicating autoimmune regulation.
  • Figure 9_ illustrates, diagramatically, the findings of this study. These are, that the adminstration of murine Mab directed against tumor associated antigens, results in the generation of an anti-mouse Ig response. Some antibodies produced in this response are against constant domain determinants of the murine Ig (1) while others are against variable domain determinants, i.e. anti-idiotypic, ( 2 ) (anti-id 1 ). Either these anti-id 1 antibodies, ( in particular those that are anti-para-topic ) or tumor associated antigen shed from targeted cells, give rise to the generation of antibodies having binding specificities similar to that of the administered murine Mab ( 3 ) i.e. anti-id 2 . In some patients, autoreactive antibodies are also generated, either, as a direct result of administering murine Ig (4b) or in response to antigenic determinants on the anti- urine Ig antibodies, ( 4a ) .
  • Figure 10 Typical antibody response of a rat (Rat 4), against the HMFG2 that was administered, and against an irrelevant mouse monoclonal antibody (11.4.1) that is of the same class and subclass with HMFG2.
  • the antibody titres are measured at serum dilution 1:10; and at various time points (before, after the 1st and after the 2nd immunisation).
  • Figure 11 The rat anti-HMFG2 and anti-11.4.1 response represented as area underneath the curve as shown in Figure 1.
  • Figure 13 Negative immunoperoxidase staining of the same as in Figure 3 section using supernatant of an irrelevant rat monoclonal antibody.
  • Figure 1 Immunoperoxidase staining of the same section as in Figures 3,4 using the HMFG2 antibody (purified).
  • Figure 15 Immunoperoxidase staining of a section using the GMN-B4 antibody (supernatant).
  • Figure 16 Negative immunoperoxidase staining of the same section as in Figure 6, using an irrelevant rat monoclonal antibody (supernatant).
  • Figure 17 Immunoperoxidase staining of the same section as in Figures 6, 7 using the HMFG2 antibody (purified).
  • Cells capable of secreting anti-idiotype antibodies may also be produced by reco binant DNA techniques.
  • nucleic acid e.g. chromosomal DNA or messenger RNA
  • PCR polymerase chain reaction
  • Appropriate expression vectors containing the coding sequences in open frame register with any necessary regulatory sequences such as promoters, initiation and termination signals are produced by conventional methods and are transfected into suitable host cells to form an expression system.
  • the host cells must be capable of expressing the coding sequences under appropriate culture conditions and will preferably (but not essentially) secrete the anti-Id 2 antibodies so produced into the culture medium from which they may be recovered by conventional techniques.
  • the human will be inoculated with an antibody as part of a therapeutic treatment.
  • Cells such as peripheral B lymphocytes will then be recovered from the blood and selected by panning using antigen bound to a solid support.
  • Cells expressing the anti-Id 2 or their surface will bind to the antigen, and are the source of the nucleic acid.
  • Amplified copies of the coding sequences are obtained using the PCR primed with nucleolide fragments having a sequence complementary to human immunoglobulin sequences and such amplified copies are used to produce the expression vectors.
  • Anti-Id 1 antibodies can themselves act as antigen, leading to an anti-Id 2 response; at least some of these anti-Id 2 antibodies (those that are anti-paratopic) will have specificity for the original antigen.
  • the generation and maintenance of such an "idiotypic network" is thought to play an important part in immune regulation (22). Pertubation of this network have been shown to lead to regulatory changes in the immune system's response to self, antigens (23-28).
  • HMFGl and HMFG2 are both murine IgGl antibodies which bind to a large mucin like molecule normally produced by the lactating breast, but also expressed by the majority (>90%) of ovarian, breast and other carcinomas of epithelial origin (29).
  • AUAl is a mouse IgGl antibody which detects an antigen expressed by a wide range of adeno-carcinomas, including approximately 75% of carcinomas of the ovary (30).
  • H17E2- is a mouse IgGl antibody directed against placental alkaline phosphatase. This enzyme is expressed as a surface membrane antigen on many neoplasms, including 60-85% of ovarian carcinomas (31). 11.41 is a mouse IgGl antibody raised against a murine la antigen (32).
  • the Ig fraction from a sample of patient 15's post 4th therapy serum was purified by protein A chromatography as follows. Serum was dialysed for 48 hr at 4°C against 0.1M phosphate buffer, pH8.0. After dialysis, the serum was incubated overnight at 4°C with protein A-linked sepha.rose 4B beads, using continuous rotation. Next day, the beads were poured into a column and the Ig depleted serum stored at 4°C for future testing.
  • the protein A column was equilibrated using O.lM phosphate buffer; this buffer was then " used to elute any unbound or non-specifically bound protein.
  • the absorbance (280nm) of the eluate was zero, the Ig fraction was eluted off the beads using O.lM citrate buffer at pH6.
  • the affinity purified Ig fraction were assayed for a) ability to bind to murine lg b) ability to inhibit the binding of the Mab to its target antigen c) molecular content using 7.5% non-reduced NaDodSO4-PAGE.
  • anti-tumour (anti-Id 2 ) antibodies Prior to assaying for the presence of anti-tumour (anti-Id 2 ) antibodies, the anti- murine Ig and anti-Id 1 antibodies were removed from patient's sera using an HMFGl (administered Mab) affinity column as previously described (18,19), and the efficiency of removal checked by ELISA. After total depletion of anti- urine Ig and anti-Id 1 antibodies, sera were then assayed for their anti-Id 2 content by ELISA using microtitre plates coated with MFG antigen (30ng/well). As positive control we used the original administered murine Mab (with specificity for the tumour antigen) and as negative control the patient's pre-therapy serum was used. The pre-therapy serum enabled assessment of pre-existing cross-reative antibodies to the MFG antigen.
  • Autoantibodies were assayed by immunofluorescence on fresh frozen tissue sections of rat liver, kidney, diaphragm and stomach. Sections were air dried, fixed in acetone and stored at -20°C. Just prior to use, sections were thawed, washed in PBS and incubated for lhr at room temperature with 50 ⁇ l of patient's serum at dilutions of 1/40, 1/80, 1/160, 1/320.
  • the inhibition assay was repeated using the affinity purified human Ig, the Ig devoid fraction and the unseparated serum from patient 15 post fourth therapy (Fig. 6). Both unfractionated serum (C) and the purified Ig fraction (E) inhibited the adminstered Mab from binding to its MFG antigen. In contrast the Ig devoid fraction (D) only inhibited by a level comparable to that shown by pre—therapy serum (B). Hence the inhibitory activity is due to antibody (anti-Id 1 ) and not to circulating antigen.
  • anti-tumor (anti-Id 2 ) antibodies we tested anti-Id 1 positive sera for increased binding to ' the MFG tumor associated antigen. Of all five patients tested, serum from patient 15 showed the greatest binding. Depletion of the anti-murine Ig activity from these sera (using an anti-mouse Ig affinity column) did not result in any significant drop in the anti-tumour activity (Fig.7). Hence the anti-tumor activity is not due to cross-reactivity of antibodies whose primary specificity i s for murine Ig .
  • Serum samples from four of the five patients positive for anti-idiotypic antibodies were positive in the frozen section auto-antibody assay (see Table 1), showing binding to connective tissue components of liver (Fig 8B). kidney glomerulus (Fig 8D) and diaphragm (Fig 8E).
  • Table 1 shows binding to connective tissue components of liver (Fig 8B).
  • Fig 8D kidney glomerulus
  • Fig 8E diaphragm
  • Our sequential study of patient 15 showed that pre-therapy, post first therapy and post second therapy sera were all negative. In contrast post third therapy serum gave intense staining (Figure B). However this patient's post fourth therapy serum was virtually negative again (Figure 8C). Thus development of auto antibodies in patient 15 was transient. No other patient received further therapy after the development of autoantibodies.
  • Anti-idiotypic antibodies identified as antibodies that bind only to the administered Mab. These could have specificity for the antigen binding site on the therapeutic antibody (anti-paratope) ; alternatively, they might detect determinants elsewhere on the variable domains (anti-idiotope) .
  • Anti-Id 1 antibodies that bind to the paratope on the administered murine anti-tumor Mab will mimic the tumor antigen and hence will form an internal .image of that antigen.
  • anti-Id 1 antibodies are produced by these patients.
  • anti-Id 1 antibodies could act as antigen and generate an anti-anti-idiotypic (anti-Id 2 ) antibody which, by definition, would be an anti-tumor antibody.
  • anti-Id 2 anti-anti-idiotypic
  • anti-tumour antibodies via the idiotypic network could be of benefit t ⁇ patients by up-regulating their immune response to their own tumor (18). Reports of tumor regression occurring long after clearance of mouse Ig suggests that anti-idiotypic antibodies may have acted as therapeutic agents (34).
  • the discovery of such antibodies has stimulated the concept of making idiotypic vaccines, and animal studies using tumor specific idiotype vaccines have already generated encouraging results (35-36).
  • Anti-Id 1 antibodies used as vaccines could stimulate the in vivo production of anti-tumor antibodies. However, the problem of using xenogeneic proteins would still be present. To overcome this, one could isolate B-cells from patients exhibiting an anti-Id 1 response and immortalise them by EBV-transformation. The EBV-transformed cell line would then be used to provide human monoclonal anti-Id 1 antibody in large amounts.
  • anti-tumour antibodies might be achieved by immunization with purified tumor antigen.
  • the lack of a good anti-tumor response in patients with cancer indicates that tumor antigen is poorly immunogenic.
  • recent advances in molecular biological techniques have permitted the isolation of the gene encoding the protein moiety of the HMFGl antigen, and in the future appropriate alteration of this gene may yield an optimally immunogenic vaccine (37).
  • the intraperitoneal route of administration of therapeutic monoclonal antibodies has the dual advantage of a high targetting efficiency and a low risk of immediate hypersensity due to circulating immune complexes (serum sickness), it may have one disadvantage: the peritoneum is an efficient site for generating an immune response - due to the high content of antigen-presenting macrophages, leading to anti-mouse Ig responses directed against both idiotypic and non-idiotypic determinants.
  • Epenetos A.A. Courtenay-Luck ' N.S. , Pickering D., Hooker G., Durbin H., Lavender J.P. and McKenzie C.G.
  • the HMFG2 monoclonal antibody was used as the immunogen.
  • This mouse IgGl recognises a mucin expressed on the T47D adenocarcinoma cell line, as well as on many ovarian, breast and colorectoral carcinomas.
  • the data is presented as area underneath the curve made of the rats response before and after the 1st and 2nd immunisation (serum dilution 1:10).
  • rat sera were tested for the presence of anti-T47D antibodies, before and during the immunisation with HMFG2.
  • Live cells were incubated with each serum, diluted 1:10 at 4 C C for lhr. The cells were.washed and incubated with a-rat Ig, iodine-125 labelled. The radioactivity was measured using a ⁇ -counter.
  • the same sera were tested against the purified mucin, using an ELISA system.
  • the antigen was coated on a 96-well plate, the sera were incubated for 2 hr, and after the plate was washed, anti-rat Ig peroxidase conjugated was added as a second layer.
  • the substrate used was again the ABTS.
  • Tissue culture supernatant was incubated with T47D cells at 4°C in the presence of HMFG2.
  • Species specific anti-mouse Ig, iodine 125 labelled was then applied, and the radioactivity was counted using a r-counter.
  • Anti-id2 In order to examine whether the above inhibition was in fact competition (suggesting the presence of rat HMFG2-like antibodies), the supernatant was further tested on T47D cells, using anti-rat Ig, iodine-125 labelled.
  • Anti-MFG membrane extract activity The purified mucin was coated on a 96-well microtiter plate, and an ELISA was performed. All positive to T47D supernatant ⁇ were tested using the same method as described above (see rat anti-tumour response).
  • Figure 10 shows a typical response (Rat4) against the HMFGl, before and after the 1st and 2nd administration.
  • the same antisera recognise to a lesser extend another antibody (11.4.1), that only has the constant region in common with HMFG2, indicating that the difference may be due to anti-idiotypic response.
  • the area under the curve was plotted for each rat, the same way as above, and is shown in Figure 11.
  • the difference between the response against the HMFG2 and the 11.4.1. indicates the presence of antibodies that recognise the hypervariable region of the HMFG2.
  • Table 2 shows the results of the Radioimmun'oassay of one of the rats sera taken at various time points against the T47D cell line. The counts are increasing with time (and subsequently with immunisations). The high background (Day -1) was within the range of all 12 unimmunised animals we tested (ranged from 25,000 to 40,000 cpm), and therefore we regarded it as normal.
  • Table 3A shows the properties of variou ⁇ supernatants in inhibiting binding of HMFG2 on the T47D cells using the Radioimmunoassay described (anti-mouse Ig iodine-125 labelled, as second layer).
  • Competition Table 3B shows the ability of the above tested supernatants to recognise the T47D Cells (anti-rat Ig iodine-125 labelled, as second layer).
  • Figures 12 and 15 show positive immunoperoxide staining of the GMN-B4 supernatant on paraffin embedded tissues.
  • Figures 13 and 16 are the negative controls and finally Figures 14 and 17 show the staining pattern of the HMFG2 on the same. Characterisation of the anti-id 2 antibody:
  • the GMN-B4 When tested the GMN-B4 was found to be a rat IgG2a.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Immunology (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)
EP89906389A 1988-05-23 1989-05-23 Antikörper Withdrawn EP0418283A1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB888812137A GB8812137D0 (en) 1988-05-23 1988-05-23 Antibodies
GB8812137 1988-05-23

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EP0418283A1 true EP0418283A1 (de) 1991-03-27

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EP89906389A Withdrawn EP0418283A1 (de) 1988-05-23 1989-05-23 Antikörper

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EP (1) EP0418283A1 (de)
JP (1) JPH03504323A (de)
AU (1) AU3698789A (de)
GB (1) GB8812137D0 (de)
WO (1) WO1989011537A1 (de)

Families Citing this family (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU704829B2 (en) 1994-12-28 1999-05-06 University Of Kentucky Murine anti-idiotype antibody 3H1
US6949244B1 (en) 1995-12-20 2005-09-27 The Board Of Trustees Of The University Of Kentucky Murine monoclonal anti-idiotype antibody 11D10 and methods of use thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8911537A1 *

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GB8812137D0 (en) 1988-06-29
WO1989011537A1 (en) 1989-11-30
JPH03504323A (ja) 1991-09-26
AU3698789A (en) 1989-12-12

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