NZ225350A - Labelled or conjugated tpa as a diagnostic or prognostic agent - Google Patents
Labelled or conjugated tpa as a diagnostic or prognostic agentInfo
- Publication number
- NZ225350A NZ225350A NZ225350A NZ22535088A NZ225350A NZ 225350 A NZ225350 A NZ 225350A NZ 225350 A NZ225350 A NZ 225350A NZ 22535088 A NZ22535088 A NZ 22535088A NZ 225350 A NZ225350 A NZ 225350A
- Authority
- NZ
- New Zealand
- Prior art keywords
- tpa
- agent
- fragment
- labelled
- tumours
- Prior art date
Links
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Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61B—DIAGNOSIS; SURGERY; IDENTIFICATION
- A61B6/00—Apparatus or devices for radiation diagnosis; Apparatus or devices for radiation diagnosis combined with radiation therapy equipment
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
- C12N9/14—Hydrolases (3)
- C12N9/48—Hydrolases (3) acting on peptide bonds (3.4)
- C12N9/50—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
- C12N9/64—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
- C12N9/6421—Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
- C12N9/6424—Serine endopeptidases (3.4.21)
- C12N9/6456—Plasminogen activators
- C12N9/6459—Plasminogen activators t-plasminogen activator (3.4.21.68), i.e. tPA
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K51/00—Preparations containing radioactive substances for use in therapy or testing in vivo
- A61K51/02—Preparations containing radioactive substances for use in therapy or testing in vivo characterised by the carrier, i.e. characterised by the agent or material covalently linked or complexing the radioactive nucleus
- A61K51/04—Organic compounds
- A61K51/08—Peptides, e.g. proteins, carriers being peptides, polyamino acids, proteins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Y—ENZYMES
- C12Y304/00—Hydrolases acting on peptide bonds, i.e. peptidases (3.4)
- C12Y304/21—Serine endopeptidases (3.4.21)
- C12Y304/21069—Protein C activated (3.4.21.69)
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2121/00—Preparations for use in therapy
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K2123/00—Preparations for testing in vivo
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Landscapes
- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Engineering & Computer Science (AREA)
- Organic Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Biomedical Technology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Zoology (AREA)
- Animal Behavior & Ethology (AREA)
- Medicinal Chemistry (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Wood Science & Technology (AREA)
- Genetics & Genomics (AREA)
- Molecular Biology (AREA)
- General Engineering & Computer Science (AREA)
- Biochemistry (AREA)
- Medical Informatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Physics & Mathematics (AREA)
- Optics & Photonics (AREA)
- Pharmacology & Pharmacy (AREA)
- Microbiology (AREA)
- Biotechnology (AREA)
- Epidemiology (AREA)
- Biophysics (AREA)
- High Energy & Nuclear Physics (AREA)
- General Chemical & Material Sciences (AREA)
- Pathology (AREA)
- Radiology & Medical Imaging (AREA)
- Heart & Thoracic Surgery (AREA)
- Surgery (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Steroid Compounds (AREA)
- Motorcycle And Bicycle Frame (AREA)
Abstract
The vehicle consists of tissue plasminogen activator or an essential part thereof and is used both for the diagnosis and therapy of malignant tumours.
Description
<div id="description" class="application article clearfix">
<p lang="en" class="printTableText">22 5 3 5 0 <br><br>
Q <br><br>
Priority D«t*(s): <br><br>
Comptott Specification <br><br>
Class: (5). <br><br>
Publication Data: 2.8..JU!I»..!?$! <br><br>
P.O. Journal, No: .\2b.<£fr.W.: <br><br>
Patents Form No. 5 <br><br>
NEW ZEALAND PATENTS ACT 1953 COMPLETE SPECIFICATION <br><br>
USE OF AN AGENT WITH A HIGH AFFINITY FOR TUMOURS <br><br>
W'- <br><br>
jf/We, BOEHRINGER INGELHEIM INTERNATIONAL GMBH, a body corporate of Federal Republic of Germany of D-6507 Ingelheim am Rhein, Federal Republic of Germany/ <br><br>
hereby declare the invention, for which we pray that a patent may be granted to jflk/us, and the method by which it is to be performed, to be particularly described in and by the following statement: <br><br>
o> <br><br>
A \ <br><br>
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8 JUL 1988 <br><br>
(followed by page la) <br><br>
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22 5^3 <br><br>
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OR 53 039 <br><br>
Use of an agent with a high affinity for tumours <br><br>
The present invention relates to an agent comprising tissue plasminogen activator ftPA) or a substantial fragment thereof for use in the diagnostic and/or prognostic investigation of tumours, and in the treatment thereof. <br><br>
In particular the present invention relates to the use of a biological agent comprising radioactively labelled tissue plasminogen activator (tPAJ for the diagnosis, location and observation of malignant tumours and to a method of scintigraphic display of malignant neoplasias using such an agent. <br><br>
Early and reliable discovery of malignant neoplastic tissue and the resulting metastases is a major criterion in the prognosis and prospect of recovery from malignant tumours. In addition to computer tomography, immune scintigraphy has more recently played an important part in the diagnostic investigation of cancers. However, this last method, which makes use of radioactively labelled antibodies, has the particular disadvantage that an antibody of this kind is capable of detecting only a very limited number of tumours of different tissues or only a specific type of tumour since, hitherto, no tumour-specific features were known and virtually every tumour has different surface antiqens. <br><br>
It is an objective of the present invention to provide an agent which could be tolerated by humans, which has a high affinity for tumour tissues and which could be used both diagnostically and/or prognostically and also therapeutically for a broad range of malignant tumours. As a solution to this <br><br>
(followed by page 2) <br><br>
- 2 - <br><br>
225 <br><br>
problem, it has surprisingly been found that radio-actively labelled tPA or substantial fraqments thereof can be used for the diagnosis, location, discovery and measurement of malignant tumours with the result that it is not only possible to diagnose tumours of different origins but also to continuously monitor their rate of response to a particular therapy instituted as a result. <br><br>
Therefore, in one aspect the present invention provides an agent for the diagnostic and/or prognostic investigation of one or more malignant tumours, comprising as tar getting agent labelled tPA or a substantial fragment thereof. <br><br>
In a further aspect the invention provides a method for the diagnostic and/or prognostic investigation of one or more malignant tumours, said method comprising administering an agent corprising labelled tPA or a fragment thereof. <br><br>
This method is faster and more sensitive and can be used with fewer restrictions than the methods of the prior art. <br><br>
In a still further aspect the invention provides use of a labelled tPA, or a fragment thereof, for the preparation of an agent for the diagnostic and/or prognostic investigation of malignant tumours. <br><br>
For immunological reasons, it is apparent to those skilled in the art that the agent according to the invention can be used species-specifically, for example human tPA can be used in humans and species-specific animal tPA can be used in veterinary medicine. <br><br>
r " «*,•<->•' • > ^ ■- ;j,^WS'Wf-vHBmi>W t„ t . ir.rrTj.--i ■■■■ .-_ <br><br>
22 5 3 5 0 <br><br>
- 3 - <br><br>
Human tPA consists of a polypeptide which occurs in single-chained and double-chained form. The published molecular weight of tPA ranqes from 66,000 to 72,000 Da depending on its origin. The N-terminal part of the tPA molecule contains two structures which resemble or correspond to the "coils" found in plasminogen and prothrombin. Moreover, this part has a region which is homologous with the "finger-like" structure in fibronectin (Banyai, <br><br>
L. et al. , FEBS Letters 163, 37-41, 1983; Pennica, <br><br>
D. et al., Nature 301, 214-221, 1983). The carboxy-terminal part of the tPA molecule shows considerable homology with other serine proteases (Strassburger, <br><br>
W. et al., PEBS Letters 157, 219-223, 1983). In addition to these coils, the finger-like structure and the active region, tPA contains a growth factor domain which shows homology with epidermal growth factor. Thus, tPA appears to be made up of a number of different functional domains each of which shows homology with other proteins (Erickson, L.A. et al., Clinics in Haematology 14, 513-530, 1985). <br><br>
It is known that tPA has a high affinity to fibrin. <br><br>
Fibrin is the chief site of attack for plasmin in thrombolysis (Wallen, P., Activation of plasminogen with urokinase and tissue activator, in: Thrombosis and urokinase (Paoletti, R., Sherry, S. eds.) Academic Press, London, 91-102, 1977) and is a component of the stroma of some tumours (Dvorak, H.F. et al., Cancer Metastasis Reviews 2, 41-73, 1983). <br><br>
On the other hand, the relative proportion of stroma and its composition varies considerably from tumour to tumour. <br><br>
Malignant tumours often contain more plasminogen activity than the corresponding normal tissue, <br><br>
although there is considerable variation in this <br><br>
izr r- - ,r"» ir{f <br><br>
(y <br><br>
22 5 35 0 <br><br>
- 4 - <br><br>
activity between histologically similar tumours (Bigbee, W.L. et al., Biochim. et Biophys. Acta 540, 285-294, 1978; Booth, N.A. et al., Blood 61, 267-275, 1983). It was therefore all the more HI unexpected that the use of labelled tPA, in particular radioactivitely labelled tPA would open up a new method, based on a new principle, for detecting a large number of tumour types by autoradiography or scintigraphy, which could be used for oncological purposes. <br><br>
There is some speculation that the plasminogen activator plays a part in regulating extracellular proteolytic activities. This activity could be responsible for the infiltration of malignant tumours through the basal membrane (Gelister, J. S. K. <br><br>
et al., B.M.J. 293, 728-731, 1986). On the other hand, there are indications that only the urokinase-like activator and not tPA has any proteolytic activity (Dan6, K., Urokinase-type plasminogen activator in cancer, XIV Annual meeting. International Society for Oncodevelopmental Biology and Medicine, Helsinki 1986, Abstract 74). <br><br>
The results according to this invention show, surprisingly clearly, that radioactively labelled tPA can specifically accumulate in malignant tumours although the mechanism and conditions affecting this binding are, as yet, unexplained. <br><br>
Thus, tPA according to the present invention is a useful vehicle and agent both for biochemical and pathological/diagnostic use and also for prognostic investigations of suspected or pre-existing malignant tumours. Moreover, the tPA which is to be used according to this invention may be labelled by known methods with known physiologically harmless or beneficial radioisotopes. <br><br>
22 5 3 5 0 <br><br>
- 5 - <br><br>
Thus, in a yet further aspect the invention provides a process for the preparation of an agent for the diagnostic and/or prognostic investigation of tumours which comprises a. isolating or preparing tPA or a fragment thereof b. labelling said material, and c. converting said labelled material into a solution which is suitable for scintigraphy. <br><br>
Conveniently, the tPA is radioactively labelled such that the radioactivity dosage range delivered following administration is between 10 and 1000 MBq. <br><br>
Particularly advantageous radioisotopes are those of iodine (e.g. ^"^1, ^2^l). Advantageously, the dosage of radioactivity to be used in the case 131 <br><br>
of I is between 10 MBq and 500 MBq, more particularly between 40 MBq and 230 MBq and, in the case 123 <br><br>
of I, between 10 MBq and 1000 MBq, more particularly between 74 and 370 MBq. Moreover, ^mTc or "*"^In or chelate-coupled metal ion isotopes may also be used for labelling. <br><br>
Radioactively labelled tPA can thus be used for scintigraphy of the whole body or of part of the body after being injected into a patient systemically (e.g. intravenously) or locally (i.e. near a suspected tumour, e.g. by i.m. route). After administration to a patient, it is possible to determine the above-mentioned diagnostic parameters of malignantly degenerate tissue, particularly tissue with a stroma component (e.g. solid tumours). Radioactively <br><br>
22 5 <br><br>
- 6 - <br><br>
labelled tPA may also be used for the prognosis of a pre-existing tumour and its development before, during or after therapeutic treatment. <br><br>
The term tPA as used herein refers to tPA prepared using known conventional cell cultures of animal or human origin or by the use of known genetic engineering techniaues, i.e. by known methods of DNA recombination. As is well known, both prokaryotic and eukaryotic cells are suitable for this latter method. <br><br>
It is preferred to use tPA or fraqments thereof which have been obtained by DNA recombination. For example, the method according to EP-A-117059, according to DE-O-3316297 or according to Collen, D., Nature 301, 214-221, 1983 may be used. <br><br>
The term tPA includes the plasminogen activator of the tissue type formed by genetically manipulated microorganisms or by correspondingly manipulated or natural cell culture systems. It is known to the average person skilled in the art that natural allelic variations occur in individual species and manifest themselves by one or more different amino acids or by different nucleotides or DNA sequences. Variations or mutations of this kind, <br><br>
which can also be produced by the known methods of DNA recombination or by controlled mutagenesis, as described for example in EP-A-93619 or EP-A-199574, include simple or multiple substitutions, deletions, additions, insertions or inversions. <br><br>
They also include tPA derivatives which contain the "coil" region characteristic of tPA and the serine protease region but are otherwise modified in one of the ways described above. According to the invention, tPA derivatives which show the <br><br>
o <br><br>
22 5 3 <br><br>
- 7 - <br><br>
characteristic activity or affinity according to the invention or a higher activity or affinity than that of native tPA may also be used (e.g. <br><br>
EP-A-93619, EP-A-199574). Thus, as used herein, <br><br>
the term tPA includes all tPA variants and derivatives. <br><br>
Moreover, it is possible to use not only radioactive tPA as a whole molecule for the purposes described but also any parts or fragments thereof which will bind to malignant tissue or to the stroma of maliqnant tumours, or variants of or chimeric molecules of the known composition of tPA. <br><br>
It has in fact been found, totally surprisingly, <br><br>
that not only the complete tPA molecule binds to tumours but also that a fragment isolated by HPLC with a size of approximately 10 kDa has a high affinity to tumour tissues. The radioactively labelled approximately 10 kDa fragments of tPA were even found to accumulate to a much greater extent in the tumour tissue than the native tPA molecule. It was also very surprising that this approximately 10 kDa fragment obviously binds to tumour sites which contain no or very little fibrin components. The evidence for this was obtained, for example, by double labelling with ^*In antifibrin and 131I-rtPA, showing that 131I-tPA binds in the peripheral part of the tumour but not in the necrotic, <br><br>
Ofibrin-containing centre of the tumour, the binding <br><br>
111 <br><br>
site of In-antifibrin. <br><br>
Therefore, even modified tPA molecules or fragments thereof are advantageous compared with proteolytically active tPA since although they have no proteolysis activity they do have a high affinity to tumour tissues. <br><br>
3 <br><br>
2253 <br><br>
The use of these "second generation" tPAs is also a part of this invention. Since the structure of tPA is known, it is possible by protein engineering to produce tPA derivatives which, for example, <br><br>
have several fingers and/or epidermal growth factor domains or which consist only of these domains or of the N-terminal. <br><br>
In another aspect the invention provides an aqent for treating one or more malignant tumours, comprising as targetting agent tPA, or a substantial fraqment thereof which is radioactively labelled and/or is conjugated to a natrual or synthetic cytostatic or cytocidal agent. <br><br>
In still another aspect, the invention provides a method for the diagnostic and/or prognostic investigation of one or more malignant tumours, said method ccrprising administering an agent, ccnprising labelled tPA or a fragment thereof. <br><br>
In yet another aspect the invention provides use of tPA, a conjugate or a fragment thereof as defined above, for the preparation of an agent for the therapeutic treatment of malignant tumours. <br><br>
In a yet still further aspect the invention provides a process for the preparation of an agent for the therapeutic treatment of tumours which comprises a. isolating or preparing tPA or a substantial fragment thereof b. radioactively labelling said material such that the radioactivity dosage delivered following administration is above 500 MBq, <br><br>
t. . <br><br>
22 5 35 <br><br>
- 9 - <br><br>
c. if desired coniuqating the material obtained according to step a. or b. with a cytostatically or cytocidallv active agent and d. converting the radioactively labelled and/or conjugated material into a suitable aaueous solution. <br><br>
The expert is currently confronted with insuperable difficulties in the controlled and effective therapeutic treatment of malignant tumours. Although in recent times monoclonal antibodies against tumours have been developed, which also serve as vehicles in conjunction with cytostatic substances - known as immunotoxins - (e.g. Biorn, M.J., Cancer Res. 46, 3262-3267, 1986), even these modern attempts at therapy have failed to solve all the problems. The remaining problems are how to achieve the desired efficiency of binding to the cell surface, how to avoid effects of neutralisation (e.g. Bjorn, <br><br>
M.J., loc. cit.), how the various types of tumour, particularly with a heterologous cell population, <br><br>
can be reached in toto, how to increase the low binding affinities of conjugated monoclonal antibodies or immunotoxins and their specificity for the tumour cells. <br><br>
It is also totally unclear whether these immunotoxins can be effective in solid tumours with a dense connective tissue component since the antibodies preferentially bind to surface antigens and do not reach cell masses located within the tumour or the centre of the tumour itself. Many of these unsolved problems are well known to those skilled in the art (e.g. Vitetta, E.S., Science, 219, 644-650, <br><br>
1983). <br><br>
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c <br><br>
- 10 - <br><br>
Due to the fact that the inventors of the present application have recognised the surprising affinity of tPA or more particularly one of the fragments thereof with tumours, the experts have been provided © with an unexpectedly new opportunity of targeting their therapy on tumours. Accordingly, tPA or substantial parts thereof must be regarded for the purposes of the invention as a agent which is not only of use in the diagnostic and/or prognostic ^ investigation of malignant tumours but also has some therapeutic importance since tPA, coupled with a known cytostatic or cytocidal agent, i.e. a synthetic or natural agent which is effective against tumour cells (e.g. ricin or other vegetable toxins, antibodies, hormones, translation inhibitors or immune modulators or parts thereof) is able to transport this agent directly to the site of a tumour. In particular, tPA fragments with a high affinity for tumours are particularly suitable, such as the 10 kDa fragment of the tPA molecule, <br><br>
which can be isolated by HPLC. For the purpose of achieving this therapeutic use, anyone skilled in the art will be familiar with a number of known and well established methods enabling him for example to produce proteins conjugated with toxins or haptens (W085/03508; Varga, J.M., in: Methods in Enzymology, 112, 259-269, 1985; Bacha, P. et al., J. Biol. <br><br>
Chem. 258, 1565-1570, 1983; Gendloff, E.H. et al., /"■"n J. Immunol. Methods 92, 15-20, 1986; Duncan, R.J.S. <br><br>
et al., Anal. Biochem. 132, 68-73, 1983; King, <br><br>
T.P. et al. , Biochemistry 2_5, 5774-5779, 1986; <br><br>
Myers, D.A. et al^. , Biochem. J. 227, 343, 1985 to name but a few). Procedures capable of conjugating tPA or substantial fragments thereof with the toxins which act against tumour cells are thus within the specialist knowledge of those skilled in the art. <br><br>
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Radioactively labelled tPA or substantial fragments <br><br>
1 <br><br>
thereof are also suitable. For example, I-labelled tPA or substantial parts thereof can be used therapeutically above a radioactivity dosaqe of 500 mbct. <br><br>
Slow-growing solid tumours, for example, do not respond well to conventional therapies because these therapies are directed against dividing cells; <br><br>
these tumours may, for example, be suitable candidates for therapy with a conjugated tPA molecule or a conjugated part of tPA as the vehicle. In such a case the advantage would be that tPA remains bound to the tumour (accumulated thereon) for a relatively long time and the conjugate acts as a cytotoxic agent continuously and guasitopically, <br><br>
targeted on the tumour tissue. Any progression or exacerbation in the tumour growth by the occurrence or recurrence of mitosis can therefore be suppressed by the therapeutic agent which is present at the site of the tumour. <br><br>
Thus, this invention opens up new possibilities for the diagnosis and treatment of cancer. <br><br>
In one study, 11 male and 4 female patients ranging from 32 to 82 years old (average 58) were investigated <br><br>
13] 1^1 <br><br>
using I-labelled tPA. The I labelling was carried out by known methods. All the patients had malignant tumours or metastases which had been verified histologically or radiologically (by X- <br><br>
ray computer tomography). The dosage of radioactivity used was within the range of 40 to 230 MBq (on average 165 MBq). After the uptake of the iodine radioisotope by the thyroid gland had been blocked by means of oral administration of sodium iodide and perchlorate (daily dose of 420 mg and 800 mg, <br><br>
respectively, for 10 days), the patients were given <br><br>
_ , _ ||( . -iini.i-in m .nmn .. <br><br>
22 5 3 5 0 <br><br>
- 12 -131 <br><br>
an intravenous iniection of I-tPA. The distribution of the radioactivity was investigated with a large-field-of-view gamma camera (crystal diameter at the top of the camera 40 cm or more) 4 and 24 hours after the injection and in three cases the recording with the gamma camera was repeated 2 to 5 days after the iniection. Computer analysis of the images obtained was carried out to determine the "target to non-target" ratio and to calculate the percentage uptake of the dosage in the target area. <br><br>
The scintigraphic results obtained from the 15 <br><br>
patients with malignant tumours or with metastases 131 <br><br>
using I-tPA are described in the Examples which follow. The relative intensity of the accumulation of radioactivity was divided into the categories of "slight", "medium" or "strong", by subjective <br><br>
131 <br><br>
assessment. In 10 cases an accumulation of I-tPA was found. In three patients the dosage administered was less than 100 MBq; with negative results in the images. 12 patients were given a dosage exceeding 100 MBq. In this group, an accumulation of radioactive tPA in the pathologically altered tissue was found in 11 patients. In four patients, there was a cerebral concentration of radioactive tPA and in eight patients the concentration was found in extracerebral areas. Figures 1 and 2 show typical results. <br><br>
Three patients showed both cerebral and extracerebral <br><br>
131 <br><br>
accumulation of I-tPA. In five patients no pathological concentration of "'"^I-tPA was observed. <br><br>
In this group, two adenocarcinoma, one hypernephroma, one prostate carcinoma and one carcinoma of the bladder had been diagnosed. <br><br>
All the accumulations were visible 24 hours and, <br><br>
except in two cases, 4 hours after the injection 1 31 <br><br>
of I-tPA. The target-to-non-target ratios 24 <br><br>
22 5 35 0 <br><br>
- 13 - <br><br>
hours after the injection, which had been determined by computer analysis of the images used for this purpose, varied from less than 1.2:1 to 2.1:1. <br><br>
In three of the patients investigated, an accumulation could still be detected five days after the iniection of 131I-tPA. <br><br>
The bio-distribution of T-tPA is shown in Fig. 3. Three minutes after the injection of ^3*I-tPA, <br><br>
there is an accumulation in the liver of 59% and in the spleen of 96% of the maximum radioactivity in the organ in question. In the liver, the maximum radioactivity was reached after 15 minutes and in the spleen after 9 minutes. After the peak had been reached, 20% of the radioactivity in the liver and 10% of the radioactivity in the spleen were eliminated within the next 15 minutes. After 24 hours the radioactivity in the liver was 2% <br><br>
and in the spleen less than 1% of the maximum value. <br><br>
Blood samples investigated by HPLC showed three 131 <br><br>
fractions of I-labelled tPA, which were designated I, II and III (Fig. 4). The approximate molecular weights of the individual fractions which were determined by means of marker proteins are as follows: 1=600 kDa, 11=80 kDa, 111=10 kDa. The plasma radioactivity fell to the same extent as in the radioactively labelled protein component II (80 kDa). <br><br>
In front of this component II a larger complex <br><br>
I (600 kDa) was found which most probably represents 131 <br><br>
a I-tPA plasminogen activator inhibitor (PAI) complex. The smallest component, which is the most interesting for the purposes of the invention as already described, namely component III with about 10 kDa had only a minimal cell-bound activity. It constituted only 0.35% of the total blood radioactivity. It was found in blood platelets and <br><br>
: C <br><br>
22 5 3 5 0 <br><br>
- 14 - <br><br>
in the lymphocyte/monocyte fraction but not in the erythrocyte fraction. The following conclusions can be drawn from this: 1. *3*I-tPA is rapidly bound to its carrier proteins and broken down into a smaller component of about 10 kDa, whilst the radioactivity found in the elution volume rapidly increases to the same extent as the radioactivity of the other components decreases (Pig. 5). 2. <br><br>
Most probably, the radioactivity accumulated by malignant tissue represents a 10 kDa metabolite of *3*I-tPA which, compared with the whole tPA molecule, is an ideal vehicle for the purposes of this invention. No undesirable side effects have been observed after administration of the radioactively labelled tPa. <br><br>
Legend relating to the drawings <br><br>
' 131 <br><br>
; Fig.l shows considerable accumulation of I-tPA <br><br>
in a brain metastasis of a lung cancer. <br><br>
Fig.2 shows considerable accumulation of ^^I-tPA in a metastasis of lung cancer in the left upper arm. <br><br>
Fig.3 shows time/activity curves of liver, heart and spleen after intravenous injection of 131I-labelled tPA (190 MBq) in a male patient a=liver, b=heart, c=spleen <br><br>
Fig.4 shows gel filtration chromatography of plasma, <br><br>
131 <br><br>
15 minutes after injection of I-tPA in patient 1 (Example 1). 1=600 kDa, 11=80 kDa, 111=10 kDa. <br><br>
22 5 3 5 0 <br><br>
- 15 - <br><br>
Pig.5 shows the HPLC runs of plasma samples after the iniection of 131I-tPA in patient 1 (Example 1), taken after various time intervals. <br><br>
a= after 15 minutes, b= after 30 minutes, <br><br>
c= after 60 minutes, d= after 150 minutes, <br><br>
e= after 240 minutes, f= after 24 hours. <br><br>
The following Examples are intended to illustrate the invention without restricting it. The intensity of the relative absorption of ^3*T-tPA (accumulation of I-tPA in various malignant primary and secondary tumours) was subdivided, by means of the scintigrams, <br><br>
into the categories of weak (1+), medium (2+) and strong (3+). The individual data concerning the various parameters measured are given in Table 1 which appears after the Examples. <br><br>
Example 1: <br><br>
Female patient, 38 years old, with cancer in the right breast and metastatic pleural effusions into both lungs, a large metastasis in the liver and two metastases in the right ovary. <br><br>
Example 2: <br><br>
Male patient, 66 years old, with cancer of the prostate diagnosed three years earlier. The initial staging was T3 NX MO, and orchiectomy and electro-resection of the prostate was performed. The patient had metastases in the left clavicular region and an irradiated 13 cm large tumour recurrency in the prostatic region. <br><br>
Example 3: <br><br>
Male patient, 65 years old, in whom a small cell cancer of the lung had been detected six months earlier which was treated with chemotherapy. After the chemotherapy, scintigraphy was performed. <br><br>
22 5 3 <br><br>
• « <br><br>
- 16 - <br><br>
At this time the patient had tumour recurrencies in the lungs and the mediastinum and brain metastasis. <br><br>
Example 4: <br><br>
Male patient, 73 years old, who had been operated on for hypernephroma 11 years earlier. Lung metastases were observed 8 years later, includinq a pituitary lesion. Scintigraphy was performed after radiotherapy to the pituitary region. <br><br>
Example 5: <br><br>
Male patient, 32 years old, with malignant melanoma of the skin which had been operated on four years earlier. At the time of scintigraphy, several subcutaneous and two cerebral metastases were detected. The patient was given interferon and regional radiation therapy. <br><br>
Example 6: <br><br>
Male patient, 70 years old, with an adenocarcinoma of the left lung hilus detected nine months earlier and treated by radiotherapy. In CT there was infiltration of the mediastinum, metastatic lymph nodes in the retrosternal and pretracheal regions and brain metastasis. <br><br>
Example 7: <br><br>
Female patient, 82 years old, with carcinoma of the bladder diagnosed 10 months earlier. Radiation therapy to the pelvic region was administered. <br><br>
At the time of examination the patient had defuse lung metastases and liver metastases. <br><br>
Example 8: <br><br>
Male patient, 69 years old, with small cell cancer of the lung which had been diagnosed 13 months earlier and treated by chemotherapy and radiotherapy <br><br>
, „„ .,. ^, ; <br><br>
22 5 3 5 0 <br><br>
- 17 - <br><br>
of the mediastinum. In CT there were two cerebral metastases. The patient also had liver metastases verified by sonographic investigation. <br><br>
Example 9: <br><br>
Male patient, 37 years old, in whom a neuroepithelioma had been removed from the skull 27 months earlier. <br><br>
A new lesion was excised from the angle of the left jaw 23 months later. Two months before the scintigraphy there was a recurrency in the left upper neck. The patient was given chemotherapy. <br><br>
Example 10: <br><br>
Male patient, 81 years old, with a tumour in the posterior part of the right pleura and pleural effusion. The tumour was 6 x 12 cm in size. Diagnosis of malignant fibrotic histiocytoma was verified by sample biopsy. There was no therapy before scintigraphy. <br><br>
Example 11: <br><br>
Male patient, 36 years old, with cancer of the stomach which had been treated by chemotherapy after an operation. Because of a stomach tumour, <br><br>
palliative gastrectomy had been carried out five months before the scintigraphy. At the time of scintigraphy, enlarged lymph nodes were found in the left clavicular region. In CT this patient had metastases in the liver, left thoracic wall and para-aortic lymph nodes. <br><br>
Example 12: <br><br>
Female patient, 47 years old, in whom a 4 mm melanoma had been removed from the right foot 2 years and 10 months earlier. Metastatic lymph nodes were found in the right inguinal region. Two metastatic lesions appeared in the left leg. These areas <br><br>
l; <br><br>
O <br><br>
22 5 3 5 0 <br><br>
- 18 - <br><br>
were Irradiated. At the time of scintigraphy, several subcutaneous metastases including a 6 x 4 cm lesion in the left thoracic wall were found. The patient was given chemotherapy. <br><br>
Example 13: <br><br>
Male patient, 48 years old, with squamous cell cancer of the oesophagus and large lymph node metastases on both sides of the neck. The lymph node metastases were treated by radiotherapy before scintigraphy. Active tumour tissue was found by autopsy in the cervical lymph nodes. <br><br>
Example 14: <br><br>
Male patient, 63 years old, in whom a squamous cell lung tumour had been operated on 8 months earlier. A cerebral metastasis was verified by CT four months after the operation and the patient was given radiotherapy. At the time of scintigraphy the patient had metastases in the left upper arm and the thoracic wall. <br><br>
Example 15: <br><br>
Female patient, 65 years old, with two malignant tumours: cancer of the breast and cancer of the rectum, both operated on 4 years earlier. The patient was admitted to hospital because of lung metastases. These were probably of rectal origin since in CT residual tumours were detected in the rectal area. <br><br>
Example 16: <br><br>
Administration of radioactive tPA <br><br>
a. 0.1 mg of tPA were radioactively labelled <br><br>
131 <br><br>
by the known iodogen method with I and an activity of 110 MBq (Fraker P.J., Speck, <br><br>
i <br><br>
.. ' ■ ■ <br><br>
22 5 3 5 0 <br><br>
- 19 - <br><br>
J.C. , Biochem. Biophys.Res.Comm. J30, 849-857, <br><br>
1978) and taken up in blood-isotonic aqueous solution. After sterile filtration, this dose of radioactively labelled tPA was injected intravenously into patients suffering from malignant tumours (melanoma, adenocarcinoma of the colon or breast or epidermal lung cancer). External whole body scintigraphy was carried out with a qamma camera 1, 2, <br><br>
4 and 7 days after the injection. <br><br>
b. 1.0 mg of tPA, radioactively labelled with with an activity of 185 MBq, was worked up as described in Example 16a and administered in the same way to the same malignant tumours. <br><br>
Whole body scintigraphy was carried out as described in Example 16a. <br><br>
Example 17: <br><br>
Bio-distribution of "^I-tPA 131 <br><br>
190 MBq of I-tPA were injected intravenously into a 22 year old male patient with treated low-grade astrozytoma. The radioactivity in the liver, <br><br>
spleen and heart was measured dynamically. Fig. 3 shows the time/activity curves obtained for the liver, heart and spleen. <br><br>
Example 18: <br><br>
Identification of the approx. 10 kDa tPA fragment <br><br>
131 <br><br>
In a dosage of 3-5 mCi/mg of protein, I-labelled <br><br>
131 <br><br>
recombinant tPA (' I-rtPA) was injected into patients and blood samples from 9 patients were tested. <br><br>
Blood samples were taken before the intravenous injection and 15, 30, 60, 150, 240 min and 24 hours after the injections and placed in EDTA test tubes <br><br>
111 ii i <br><br>
22 5 350 <br><br>
o <br><br>
- 20 - <br><br>
in known manner. The plasma and blood cells were then removed immediately by centrifuging. Blood platelets and the lymphocyte/monocyte fraction were separated by known methods using L12UK0PREPR test tubes. HPLC exclusion chromatography (gel filtration of the plasma) was carried out under the following conditions: <br><br>
u <br><br>
ApDaratus: <br><br>
UV Detector: <br><br>
Preliminary column: Column: <br><br>
Fraction collector: HPLC buffer: <br><br>
Flow rate: <br><br>
Wavelength: Gamma detector: <br><br>
Samples: <br><br>
Gel filtration: <br><br>
LKB 2150 HPLC Pump + LKB <br><br>
2.152 controller <br><br>
LKB 2151, variable wavelenqth monitor <br><br>
Ultropac TSK SWP (7.5 x 75mm) LKB Ultropac TSK G300SW (7.5 x 300mm) LKB LKB 2212 Helirac 20 mmol/1 L-arginine, 11 mmol/1 phosphoric acid, 0.05% sodium azide, pH 7.3 <br><br>
0.75 ml/min, 1 minute fractions were collected 280 nm <br><br>
Beckman Model 170 Radioisotope Detector and Compugamma Model 1282, LKB Wallac The plasma samples were diluted 1:10 with HPLC buffer and filtered before injection onto the column Absorption of the eluate was recorded at 280 nm and the radioactivity was also measured using a gamma counter <br><br>
Table It <br><br>
1 •"! 1 <br><br>
Accumulation of J I-tPA in various malignant primary and secondary tumours. <br><br>
131 <br><br>
The intensity of the relative uptake of I-tPA was graded, by means of the scintigrams obtained, as weak (1+), medium (2+) and strong (3+). <br><br>
Example No. Age (Patient) <br><br>
Sex <br><br>
Diagnosis <br><br>
1 <br><br>
2 <br><br>
4 <br><br>
5 <br><br>
38 66 <br><br>
65 <br><br>
73 32 <br><br>
131I-tPA Dose [MBq] <br><br>
F M <br><br>
M <br><br>
M M <br><br>
Breast cancer Metastatic cancer of prostate Small cell cancer of the lung; with brain metastases <br><br>
37 181 <br><br>
200 <br><br>
100 <br><br>
Hypernephroma Malignant melanoma; 155 with 2 metastases <br><br>
Intensity Target-to- Time after <br><br>
(relative non-target injection of uptake of ratio ^"3*I-tPA [h] 131I-tPA) <br><br>
negative negative <br><br>
1+ <br><br>
1+ <br><br>
negative 1+, 2+ <br><br>
1.3 1.3 <br><br>
1.3 1.5 1.3 <br><br>
4 24 <br><br>
4 <br><br>
24 48 <br><br>
I <br><br>
o o <br><br>
Example No. Age Sex Diagnosis <br><br>
(Patient) <br><br>
6 70 M Bronchial cancer; <br><br>
brain metastasis <br><br>
7 82 F Cancer of the bladder; <br><br>
diffuse lung metastases <br><br>
8 69 M Small cell lung cancer; <br><br>
brain metastases <br><br>
9 37 M Neuroepithelioma on the neck <br><br>
10 81 M Histocytoma of the pleura <br><br>
11 36 M Adenocarcinoma of the stomach; metastasis in the left thoracic wall f \ j <br><br>
O <br><br>
131 <br><br>
I-tPA Intensity Target-to- Time after <br><br>
Dose (relative non-target injection of upt< <br><br>
131, <br><br>
i 31 <br><br>
[MBq] uptake of ratio I-tPA [h] <br><br>
"I-tPA) <br><br>
174 1+ <br><br>
1+ 1.3 <br><br>
67 negative <br><br>
233 <br><br>
2+, 3+ 1.4 4 <br><br>
1.7 <br><br>
181 2+ 1.4 4 <br><br>
1.7 24 £ <br><br>
192 1+ 1.2 <br><br>
185 1.2 <br><br>
1+ <br><br>
ro <br><br>
CJI Ca| Ol <br><br>
0 <br><br>
1 <br><br>
o <br><br>
Example No. Age Sex Diagnosis (Patient) <br><br>
12 47 F Malignant melanoma metastasis in the left thoracic wall <br><br>
13 48 M Squamous cell cancer of the oesophagus; metastasis on the left side of the neck <br><br>
14 63 M Lunq cancer; <br><br>
metastasis in the 1 upper left arm <br><br>
15 65 F Multiple lung metastasis; <br><br>
primary tumour unknown <br><br>
O <br><br>
9 <br><br>
1^1 <br><br>
I-tPA Intensity Target-to- Time after Dose (relative non-target injection of <br><br>
UPti <br><br>
131, <br><br>
[MBq] uptake of ratio ^"^I-tPA [h] <br><br>
I-tPA) <br><br>
229 1.3 24 <br><br>
3+ <br><br>
185 <br><br>
3+ 1.7 24 <br><br>
185 ^ <br><br>
WT <br><br>
3+ 1.4 4 <br><br>
2.1 24 <br><br>
215 1+ 1.2 24 <br><br>
ro ro oi <br><br>
04 CJI <br><br></p>
</div>
Claims (1)
- <div id="claims" class="application article clearfix printTableText"> <p lang="en"> 225350<br><br> -24-<br><br> WHAT WE CLAIM IS;<br><br> 1. An agent suitable for the diagnostic and/or prognostic 5 investigation of one or more malignant tumours, comprising labelled tPA or a substantial fragment thereof.<br><br> 2. An agent as claimed in claim l, wherein said tPA or fragment thereof is of natural origin and has been<br><br> 10 isolated from a eukaryotic cell culture.<br><br> 3. An agent as claimed in claim 1, wherein said tPA or fragment thereof originates from transformed prokaryotic or eukaryotic cells.<br><br> 15<br><br> 4. An agent as claimed in any one of claims 1 to 3,<br><br> wherein said tPA or fragment thereof comprises at least one tumour-binding component and has substantially no proteolytic activity.<br><br> 20<br><br> 5. An agent as claimed in any one of claims 1 to 4,<br><br> wherein said tPA or fragment thereof is a derivative derived from a tPA-encoding polynucleotide by controlled mutagenesis and which has a characteristic activity or<br><br> 25 affinity to tumour tissues at least equal to that of the original tPA or fragment thereof.<br><br> 6. An agent as claimed in any one of claims l to 5,<br><br> wherein said tPA or fragment thereof is a variant<br><br> 30 derived from an organism having multiple alleles or exhibiting tPA polymorphism.<br><br> 7. An agent as claimed in any one of claims 1 to 6,<br><br> wherein said tPA is a tPA allelic variant, or a 35 derivative or a fragment thereof which has at least one finger-like structure and/or epidermal growth factor domain or consists only of at least one of these N—&<br><br> terminal parts or of combinations of these parts. j,-\f ^<br><br> T2 9 APR 1991^<br><br> <0./<br><br> *w • ~ "" ' """""<br><br> £ i<br><br> O<br><br> O<br><br> 225350<br><br> - 25 -<br><br> ^ 8. An agent as claimed in any one of claims 1 to 7,<br><br> comprising a tPA fragment having a size of the order of ^ 10 kDa.<br><br> I (3 5 9. An agent as claimed in claim 8, wherein said tPA fragment<br><br> \ has a size of about 10 kDa and substantially does not bind to<br><br> | fibrin.<br><br> t<br><br> I<br><br> !<br><br> 1 10. An agent as claimed in any one of claims 1 to 9,<br><br> | 10 wherein said tPA or fragment thereof is radioactively<br><br> | labelled.<br><br> 11. An agent as claimed in claim 1 Cv wherein said tPA or fragment thereof is radioactively labelled with "XI, "'I, 15 **"Tc and/or X11ln.<br><br> 12; An agent comprising labelled tPA, or a fragment thereof as claimed in any one of claims 1 to 11, which is suitable for administration by a systemic route.<br><br> 20<br><br> 25<br><br> 13. An agent comprising labelled tPA, or a fragment thereof as claimed in any one of claims 1 to 11, which is suitable for administration locally into or onto the malignant tumour.<br><br> 1.4. An agent as claimed in claim l, substantially as described herein.<br><br> ■15. Use of a labelled tPA, or a fragment thereof, for<br><br> ?• M ><br><br> 30 the preparation of an agent for the diagnostic and/bij.'1 &<br><br> r"<br><br> CV.<br><br> prognostic investigation of malignant tumours.<br><br> •j<br><br> 35<br><br> TT , . „ . . . ,, , . _ „ \ 29APR 1991 v/<br><br> 16. use as claimed in claim 151 substantially as ;<br><br> <\ /<br><br> described herein. V-<br><br> 17. An agent suitable for treating one or more malignant tumours, comprising as targetting agent tPA, or a substantial fragment thereof, which is radioactively labelled and/or is conjugated to a natural or synthetic cytostatic or cytocidal agent.<br><br> ?253?0<br><br> - 26 -<br><br> 18. An agent as claimed in claim 17, wherein said tPA or fragment thereof is as defined in any one of claims 2 to 8.<br><br> 19. An agent as claimed in claim 17, wherein said tPA or 5 fragment thereof is as defined in claim 9.<br><br> 20. An agent as claimed in any one of claims 17 to 19, wherein said tPA, conjugate, or fragment thereof, is radioactively labelled.<br><br> 1° 21. An agent as claimed in claim 20, wherein the dosage of radioactivity delivered following administration is above 500 MBq.<br><br> 22. An agent as claimed in any one of claims 17 to 21,<br><br> 15 which is suitable for administration by a systemic route.<br><br> 23. An agent as claimed in any one of claims 17 to 21,<br><br> which is suitable for administration locally into or<br><br> 20 onto the malignant tumour.<br><br> 24. An agent as claimed in claim 17., substantially as described herein.<br><br> 25 25. Use of tPA, a conjugate or a fragment thereof as defined in claim 17, for the preparation of an agent for the therapeutic treatment of malignant tumours.<br><br> 26. Use as claimed in claim 2b, substantially as 30 described herein.<br><br> 27. A process for the preparation of an agent for the diagnostic and/or prognostic investigation of tumours as defined in any one of claims 1 to 13, which comprises<br><br> 35<br><br> a.<br><br> isolating or preparing tPA or a fragment thereof^*<br><br> b. labelling said material, and<br><br> :! ■ Oii<br><br> If 2 9 APR 19911<br><br> r\<br><br> c. converting said labelled material into a solution which is suitable for scintigraphy.<br><br> 22SISO<br><br> 27<br><br> 28. A process as claimed in claim 27, wherein said material is radioactively labelled such that the radioactivity dosage range delivered following administration is between 10 and 1000 MBq.<br><br> 29%• A process as claimed in claim 27, substantially as described herein.<br><br> 30. An agent for the diagnostic and for prognostic investigation of tumours prepared by the process as claimed in claim 27 and which is suitable for infusion or injection.<br><br> 31. A process for the preparation of an agent for the therapeutic treatment of tumours as defined in any one of claims 17 to 24 which comprises a. isolating or preparing tPA or a substantial fragment thereof b. radioactively labelling said material such that the radioactivity dosage delivered following administration is above 500 MBq,<br><br> c. if desired conjugating the material obtained according to step a. or b. with a cytostatically or cytocidally active agent and d. converting the radioactively labelled and/or conjugated material into a suitable aqueous solution.<br><br> 32. A process as claimed in claim 31, substantially as described herein.<br><br> 33. An agent for the therapeutic treatment of tumours prepared by the process as claimed in claim 31 which is suitable for infusion or injection.<br><br> 225350<br><br> -28-<br><br> 34. A method for the diagnostic and/or prognostic investigation of one or more malignant tumours in a non-human body, said method comprising administering an agent as defined in any one of claims 1 to 13.<br><br> O<br><br> o o<br><br> 35. A method as claimed in claim 34, substantially as described herein.<br><br> 36. A method for the treatment of tumours in the non-human body, said method comprising administering to said body an agent as defined in any.one of claims 1 to 13.<br><br> 37. A method as claimed in claim 36, substantially as described herein.<br><br> BOEHRINGER INGELHEIM INTERNATIONAL GMBH<br><br> a by t<br><br> A<br><br> eir attorneys<br><br> BALDWIN. SON & CAREY<br><br> ii*<br><br> fY .. r I<br><br> ft *•*" \<br><br> 29 APR 1991<br><br> r'".|<br><br> </p> </div>
Applications Claiming Priority (1)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19873722522 DE3722522A1 (en) | 1987-07-08 | 1987-07-08 | USE OF A VEHICLE WITH HIGH AFFINITY TO TUMORS |
Publications (1)
Publication Number | Publication Date |
---|---|
NZ225350A true NZ225350A (en) | 1991-07-26 |
Family
ID=6331118
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
NZ225350A NZ225350A (en) | 1987-07-08 | 1988-07-08 | Labelled or conjugated tpa as a diagnostic or prognostic agent |
Country Status (13)
Country | Link |
---|---|
EP (1) | EP0298436B1 (en) |
JP (1) | JPH01125331A (en) |
KR (1) | KR890001508A (en) |
AT (1) | ATE81473T1 (en) |
AU (1) | AU623080B2 (en) |
DE (2) | DE3722522A1 (en) |
DK (1) | DK167561B1 (en) |
ES (1) | ES2046244T3 (en) |
FI (1) | FI883177A (en) |
GR (1) | GR3006404T3 (en) |
NO (1) | NO883040L (en) |
NZ (1) | NZ225350A (en) |
ZA (1) | ZA884870B (en) |
Family Cites Families (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
ZA831399B (en) * | 1982-03-05 | 1984-02-29 | Health Lab Service Board | New fibrinolytic enzymes and methods for their production and pharmaceutical compositions containing them |
US4663146A (en) * | 1983-07-29 | 1987-05-05 | Codon Genetic Engineering Laboratories | Methods and compositions for the diagnosis of bloodclots using plasminogen activator |
-
1987
- 1987-07-08 DE DE19873722522 patent/DE3722522A1/en not_active Withdrawn
-
1988
- 1988-07-04 FI FI883177A patent/FI883177A/en not_active IP Right Cessation
- 1988-07-06 AT AT88110746T patent/ATE81473T1/en not_active IP Right Cessation
- 1988-07-06 DE DE8888110746T patent/DE3875290D1/en not_active Expired - Fee Related
- 1988-07-06 EP EP88110746A patent/EP0298436B1/en not_active Expired - Lifetime
- 1988-07-06 ES ES198888110746T patent/ES2046244T3/en not_active Expired - Lifetime
- 1988-07-07 JP JP63169997A patent/JPH01125331A/en active Pending
- 1988-07-07 NO NO88883040A patent/NO883040L/en unknown
- 1988-07-07 ZA ZA884870A patent/ZA884870B/en unknown
- 1988-07-07 DK DK377588A patent/DK167561B1/en not_active IP Right Cessation
- 1988-07-08 AU AU18895/88A patent/AU623080B2/en not_active Ceased
- 1988-07-08 KR KR1019880008468A patent/KR890001508A/en not_active Application Discontinuation
- 1988-07-08 NZ NZ225350A patent/NZ225350A/en unknown
-
1992
- 1992-12-02 GR GR920402768T patent/GR3006404T3/el unknown
Also Published As
Publication number | Publication date |
---|---|
EP0298436B1 (en) | 1992-10-14 |
JPH01125331A (en) | 1989-05-17 |
DK167561B1 (en) | 1993-11-22 |
EP0298436A3 (en) | 1990-01-17 |
DK377588A (en) | 1989-01-09 |
DE3875290D1 (en) | 1992-11-19 |
ES2046244T3 (en) | 1994-02-01 |
FI883177A (en) | 1989-01-09 |
ATE81473T1 (en) | 1992-10-15 |
DK377588D0 (en) | 1988-07-07 |
DE3722522A1 (en) | 1989-01-19 |
KR890001508A (en) | 1989-03-27 |
AU1889588A (en) | 1989-01-12 |
FI883177A0 (en) | 1988-07-04 |
ZA884870B (en) | 1989-04-26 |
GR3006404T3 (en) | 1993-06-21 |
NO883040L (en) | 1989-01-09 |
NO883040D0 (en) | 1988-07-07 |
AU623080B2 (en) | 1992-05-07 |
EP0298436A2 (en) | 1989-01-11 |
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