ZA200101574B - Bifunctional antibodies and their use in targeting anti-tumour agents. - Google Patents
Bifunctional antibodies and their use in targeting anti-tumour agents. Download PDFInfo
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- ZA200101574B ZA200101574B ZA200101574A ZA200101574A ZA200101574B ZA 200101574 B ZA200101574 B ZA 200101574B ZA 200101574 A ZA200101574 A ZA 200101574A ZA 200101574 A ZA200101574 A ZA 200101574A ZA 200101574 B ZA200101574 B ZA 200101574B
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- South Africa
- Prior art keywords
- antibody according
- antibody
- hydroxy
- radiolabelled
- molecule
- Prior art date
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- 230000001588 bifunctional effect Effects 0.000 title claims description 10
- 230000000259 anti-tumor effect Effects 0.000 title description 4
- 230000008685 targeting Effects 0.000 title description 4
- 206010028980 Neoplasm Diseases 0.000 claims description 18
- 239000003795 chemical substances by application Substances 0.000 claims description 11
- YBJHBAHKTGYVGT-ZKWXMUAHSA-N (+)-Biotin Chemical compound N1C(=O)N[C@@H]2[C@H](CCCCC(=O)O)SC[C@@H]21 YBJHBAHKTGYVGT-ZKWXMUAHSA-N 0.000 claims description 10
- 239000003814 drug Substances 0.000 claims description 8
- 108090000790 Enzymes Proteins 0.000 claims description 6
- 102000004190 Enzymes Human genes 0.000 claims description 6
- 239000000427 antigen Substances 0.000 claims description 6
- 102000036639 antigens Human genes 0.000 claims description 6
- 108091007433 antigens Proteins 0.000 claims description 6
- 229940124597 therapeutic agent Drugs 0.000 claims description 6
- 229960002685 biotin Drugs 0.000 claims description 5
- 235000020958 biotin Nutrition 0.000 claims description 5
- 239000011616 biotin Substances 0.000 claims description 5
- 230000001225 therapeutic effect Effects 0.000 claims description 5
- 238000001727 in vivo Methods 0.000 claims description 4
- 238000000034 method Methods 0.000 claims description 4
- ULCDEQBOSVFJBR-UHFFFAOYSA-N 4,4-bis(4-hydroxy-3,5-diiodophenyl)pentanoic acid Chemical compound C=1C(I)=C(O)C(I)=CC=1C(CCC(O)=O)(C)C1=CC(I)=C(O)C(I)=C1 ULCDEQBOSVFJBR-UHFFFAOYSA-N 0.000 claims description 3
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical compound [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 claims description 3
- 108010022366 Carcinoembryonic Antigen Proteins 0.000 claims description 3
- 150000001875 compounds Chemical class 0.000 claims description 3
- 239000000032 diagnostic agent Substances 0.000 claims description 3
- 229940039227 diagnostic agent Drugs 0.000 claims description 3
- 238000004519 manufacturing process Methods 0.000 claims description 3
- QYFLDPNTDXMLRO-UHFFFAOYSA-N n-(6-aminohexyl)-2-hydroxy-3,5-diiodobenzamide Chemical compound NCCCCCCNC(=O)C1=CC(I)=CC(I)=C1O QYFLDPNTDXMLRO-UHFFFAOYSA-N 0.000 claims description 3
- 230000007935 neutral effect Effects 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 2
- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 2
- ZWVIEGKRECXIPC-UHFFFAOYSA-N n-(6-aminohexyl)-4-hydroxy-3,5-diiodobenzamide Chemical compound NCCCCCCNC(=O)C1=CC(I)=C(O)C(I)=C1 ZWVIEGKRECXIPC-UHFFFAOYSA-N 0.000 claims description 2
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 2
- 102000012406 Carcinoembryonic Antigen Human genes 0.000 claims 1
- 239000002253 acid Substances 0.000 claims 1
- 201000011510 cancer Diseases 0.000 claims 1
- 238000003745 diagnosis Methods 0.000 claims 1
- SYECJBOWSGTPLU-UHFFFAOYSA-N hexane-1,1-diamine Chemical compound CCCCCC(N)N SYECJBOWSGTPLU-UHFFFAOYSA-N 0.000 claims 1
- 239000011630 iodine Substances 0.000 claims 1
- 238000002560 therapeutic procedure Methods 0.000 claims 1
- 231100000433 cytotoxic Toxicity 0.000 description 10
- 230000001472 cytotoxic effect Effects 0.000 description 10
- 239000002254 cytotoxic agent Substances 0.000 description 8
- 229940127089 cytotoxic agent Drugs 0.000 description 8
- 231100000599 cytotoxic agent Toxicity 0.000 description 7
- 229940002612 prodrug Drugs 0.000 description 5
- 239000000651 prodrug Substances 0.000 description 5
- 108060003951 Immunoglobulin Proteins 0.000 description 3
- 239000012634 fragment Substances 0.000 description 3
- 102000018358 immunoglobulin Human genes 0.000 description 3
- 230000003993 interaction Effects 0.000 description 3
- 102000004169 proteins and genes Human genes 0.000 description 3
- 108090000623 proteins and genes Proteins 0.000 description 3
- 102100025475 Carcinoembryonic antigen-related cell adhesion molecule 5 Human genes 0.000 description 2
- 102000017727 Immunoglobulin Variable Region Human genes 0.000 description 2
- 108010067060 Immunoglobulin Variable Region Proteins 0.000 description 2
- 241000124008 Mammalia Species 0.000 description 2
- 108020004511 Recombinant DNA Proteins 0.000 description 2
- 241000283984 Rodentia Species 0.000 description 2
- 108010090804 Streptavidin Proteins 0.000 description 2
- 229940127121 immunoconjugate Drugs 0.000 description 2
- 230000002163 immunogen Effects 0.000 description 2
- PNDPGZBMCMUPRI-UHFFFAOYSA-N iodine Chemical compound II PNDPGZBMCMUPRI-UHFFFAOYSA-N 0.000 description 2
- 230000004807 localization Effects 0.000 description 2
- 239000002184 metal Substances 0.000 description 2
- 231100000252 nontoxic Toxicity 0.000 description 2
- 230000003000 nontoxic effect Effects 0.000 description 2
- 230000035515 penetration Effects 0.000 description 2
- 238000002823 phage display Methods 0.000 description 2
- 239000000546 pharmaceutical excipient Substances 0.000 description 2
- 238000002360 preparation method Methods 0.000 description 2
- 238000000163 radioactive labelling Methods 0.000 description 2
- 230000001988 toxicity Effects 0.000 description 2
- 231100000419 toxicity Toxicity 0.000 description 2
- 241000283690 Bos taurus Species 0.000 description 1
- 241000283707 Capra Species 0.000 description 1
- 102000005367 Carboxypeptidases Human genes 0.000 description 1
- 108010006303 Carboxypeptidases Proteins 0.000 description 1
- KCXVZYZYPLLWCC-UHFFFAOYSA-N EDTA Chemical compound OC(=O)CN(CC(O)=O)CCN(CC(O)=O)CC(O)=O KCXVZYZYPLLWCC-UHFFFAOYSA-N 0.000 description 1
- 241000724791 Filamentous phage Species 0.000 description 1
- 241000282412 Homo Species 0.000 description 1
- -1 I'*’ Chemical compound 0.000 description 1
- 108091007491 NSP3 Papain-like protease domains Proteins 0.000 description 1
- 241001494479 Pecora Species 0.000 description 1
- 108010039491 Ricin Proteins 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 208000009956 adenocarcinoma Diseases 0.000 description 1
- 239000002246 antineoplastic agent Substances 0.000 description 1
- 230000009286 beneficial effect Effects 0.000 description 1
- 230000015572 biosynthetic process Effects 0.000 description 1
- QKSKPIVNLNLAAV-UHFFFAOYSA-N bis(2-chloroethyl) sulfide Chemical class ClCCSCCCl QKSKPIVNLNLAAV-UHFFFAOYSA-N 0.000 description 1
- 239000013522 chelant Substances 0.000 description 1
- 239000002738 chelating agent Substances 0.000 description 1
- 238000007796 conventional method Methods 0.000 description 1
- 238000010494 dissociation reaction Methods 0.000 description 1
- 230000005593 dissociations Effects 0.000 description 1
- 229940079593 drug Drugs 0.000 description 1
- 210000004408 hybridoma Anatomy 0.000 description 1
- BHEPBYXIRTUNPN-UHFFFAOYSA-N hydridophosphorus(.) (triplet) Chemical compound [PH] BHEPBYXIRTUNPN-UHFFFAOYSA-N 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 230000028993 immune response Effects 0.000 description 1
- 238000001990 intravenous administration Methods 0.000 description 1
- 210000003734 kidney Anatomy 0.000 description 1
- 238000011031 large-scale manufacturing process Methods 0.000 description 1
- 239000003446 ligand Substances 0.000 description 1
- 230000007774 longterm Effects 0.000 description 1
- 230000003472 neutralizing effect Effects 0.000 description 1
- 230000008569 process Effects 0.000 description 1
- 241000894007 species Species 0.000 description 1
- 238000003786 synthesis reaction Methods 0.000 description 1
- 210000005166 vasculature Anatomy 0.000 description 1
Classifications
-
- 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
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
-
- 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
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/30—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
- C07K2317/31—Immunoglobulins specific features characterized by aspects of specificity or valency multispecific
Landscapes
- Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Organic Chemistry (AREA)
- Medicinal Chemistry (AREA)
- General Health & Medical Sciences (AREA)
- Immunology (AREA)
- Veterinary Medicine (AREA)
- Genetics & Genomics (AREA)
- Animal Behavior & Ethology (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Public Health (AREA)
- Pharmacology & Pharmacy (AREA)
- Molecular Biology (AREA)
- Biochemistry (AREA)
- Biophysics (AREA)
- General Chemical & Material Sciences (AREA)
- Chemical Kinetics & Catalysis (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Cell Biology (AREA)
- Physics & Mathematics (AREA)
- Optics & Photonics (AREA)
- Epidemiology (AREA)
- Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
- Peptides Or Proteins (AREA)
Description
BIFUNCTIONAL ANTIBODIES AND THEIR USE IN
TARGETING ANTI-TUMOUR AGENTS
This invention relates to bifunctional antibodies and to their use in targeting anti-tumour agents in vivo.
The targeting of therapeutic agents to particular sites in vivo, is well known. In particular, it is very desirable to target anti-cancer agents to a tumour site, to increase the concentration of the agent at the site and thereby improve its effectiveness in neutralising the tumour. Examples of agents that target tumours are well known, many of these relying on the specificity of monoclonal antibodies for delivering the diagnostic or therapeutic agent to the target site. One approach has been to use a radionuclide-antibody conjugate which localises at a target tissue where the radionuclide may . exert its cytotoxic effect. : However, it has been shown that there are problems with the utility of radionuclide-antibody conjugates, for . example poor penetration of the conjugates to the target site owing to the high molecular weight of the conjugate.
In addition, for the conjugate to be therapeutically effective, it must be given time to localise at the target site. The radionuclide is therefore present in the body for prolonged periods, and this results in undesirable toxicity at non-target sites.
It is therefore desirable to administer the antibodies independently of the cytotoxic radiolabelled agent, allowing the antibody to localise at the target site before administering the cytotoxic radiolabelled agent.
US-A-5630996 describes one approach that uses antibody-streptavidin conjugates to target a radionuclide- labelled biotin. Streptavidin has high affinity for biotin and is able to localise the radionuclide at the target site through the biotin-streptavidin interaction. However, streptavidin is a protein that is immunogenic in humans and consequently may not be suitable for repeated long-term therapeutic use.
US-a-559.828 discloses bispecific antibodies that have affinity for metal chelates and for a particuiar protein epitope. However, the chelates, EDTA-Y and DTPA-Y* preferably require the covalent addition of a fos-peptide which interacts with a jun-peptide on the antibody, to localise sufficient Y¥*° to the target site. In addition, dissociation may occur between the chelating agent (EDTA) and the radionuclide (Y¥°°). Therefore, localisation at the tumour site may not be efficient, and the process of producing the fos-peptide-metal chelate conjugate is lengthy and unsuitable for large-scale manufacture. .
The present invention relates to bifunctional . antibodies which have affinity for both an antigen present at a tumour site, and for a therapeutic or diagnostic agent, wherein the agent is an organic molecule that is radiolabelled or is covalently bound to a cytotoxic agent.
In a separate embodiment, the organic molecule is bound to an enzyme capable of converting a prodrug into a cytotoxic form.
The invention therefore provides a means for increasing the localisation of a therapeutic agent at a target site in a mammal, by the sequential administration of the bifunctional antibody and the organic molecule. The
® WO 00/14119 PCT/GB99/02938 invention may have use in therapeutic or diagnostic applications.
Typically, the organic molecule is biotin or an organic molecule which exhibits good penetration at a target site and otherwise neutral biodistribution in vivo.
One of the advantages of the present invention, is that it is possible to administer a cytotoxic agent which will localise at the desired target due to the interaction with antibody, but which will have reduced toxicity to non- target tissues, as unbound agent will be cleared efficiently from the body.
In one embodiment, the cytotoxic agent is a radionuclide, and is covalently linked to the organic molecule, or is itself part of the organic molecule. The radionuclide may be chosen to provide a therapeutic effect, e.g. as an anti-tumour agent, or may be administered for . diagnostic purposes, e.g. tumour imaging.
In another embodiment, the organic molecule is linked p to an enzyme that can be used to convert a suitable prodrug into an active cytotoxic form.
The antibodies of the present invention may be produced using conventional techniques, for example, hybridoma synthesis, recombinant DNA techniques or phage display. The antibodies may be derived from any species, including rodent, although it is preferred that the antibodies are derived from mammals other than rodents, e.g. sheep, goats or cows, to generate high-affinity antibodies.
Typically, the antibodies will have an affinity of at least 10'° 1/mol, preferably 10! 1/mol, more preferably 10%?
1/mol and most preferably 10" 1/mol for the respective ligands.
A bifunctional antibody according to the invention may be whole antibody or may be a fragment thereof, e.g. f(ab),. In a further embodiment, the antibody may comprise two single chain fv fragments. The preparation of bifunctional sFvs is well known. For example, Carter et al.. Current Opinion in Biotechnology 1997, 8: 449-454, discloses the production of bifunctional sFvs using phage display libraries.
In addition, the antibodies may be modified by recombinant DNA techniques to "humanise” the antibodies, making them less immunogenic when administered to a patient. The humanised antibody should comprise at least the hypervariable region from both a monoclonal antibody having affinity for target antigen, and a monoclonal antibody having affinity for the organic molecule. The remainder of the antibody variable region may be of human immunoglobulin. A higher proportion of human . immunoglobulin may be present in a whole antibody or a fragment, e.g. F(ab'),. When a single-chain Fv fragment is : used, the fragment may comprise hypervariable regions as described above and, optionally, the variable framework from human immunoglobulin.
The antibody will have affinity for a particular target site. Typically, the target site will be a tumour and the antibody will have affinity for a tumour-associated antigen. An example of a tumour-associated antigen is the carcinoembryonic antigen (CEA) which is found on colorectal tumours and other adeno-carcinomas.
In the preferred embodiment, the antibody has ligand- affinity for an organic molecule that is radiolabelled.
The invention encompasses both the separate covalent attachment of a radionuclide to an organic molecule, and additionally the simple radiolabelling of a suitable atom on the organic molecule itself. For example, the organic 5 molecule may comprise a phosphorous or iodine atom which is radiolabelled to provide a cytotoxic organic molecule.
Administration of the molecule will 1localise the radionuclide at a tumour site through binding to the antibody to exert a cytotoxic effect on the tumour.
Radionuclides having a cytotoxic effect are well known. A preferred radionuclide that may be used in the invention is a radioisotope of iodine, e.g. I'*’, I'** and I'*® which may be used for diagnostic purposes and I'*' which may be used in therapeutics. A further preferred radionuclide that may be used in the invention, is P*.
The cytotoxic agent may also be a cytotoxic drug, e.g. ricin or calicheamycin.
In an alternative embodiment, the organic molecule is } linked (conjugated) to an enzyme. The enzyme is capable of converting a suitable prodrug into an active cytotoxic form. The term "prodrug" is used herein to define an inactive form of a drug which may be cleaved by enzymic action to release the therapeutically-active form.
Suitable enzyme-prodrug systems are known to those skilled in the art and include carboxypeptidases and modified mustard gas derivatives.
The organic molecules that are useful in the present invention must be capable of specific interaction with an antibody. The molecules must therefore be of a sufficient size to elicit an immune response for the production of the antibodies when conjugated to a protein carrier, or be of a sufficient size to facilitate antibody creation from antibody libraries, e.g. displayed on filamentous phage.
Preferably, the organic molecules linked to the cytotoxic agent or enzyme are capable of passing through the lining of the vasculature to reach the target site. The molecular weight of the organic molecules is preferably less than 1500, more preferably less than 1000. The organic molecules are preferably non-toxic when not radiolabelled.
In addition, the labelled organic molecules should have a neutral biodistribution when administered TC a patient in the absence cf bispecific antibody, and it is preferable if molecules are chosen which do not accumulate xn the tavroid and are rapidly cleared through the kidney. It is also beneficial if the molecules are easily derived from a non- : labelled parent molecule and that the derived, labelled : 15 molecule is stable following administration. The conjugate should preferably be water-soluble, to facilitate preparation in suitable excipients. Suitable organic molecules include non-toxic compounds, although the molecules may be made cytotoxic by radiolabelling. :
In a preferred embodiment, the radio-labelled organic molecule is radio-labelled biotin. In a further preferred embodiment, the molecule is of formula I 0
Me : OH
I
OE (1)
I 1 i.e. 4,4-bis(4-hydroxy-3,5-diiodophenyl)pentanoic acid.
In a further preferred embodiment, the molecule is of formula II ‘
fo)
R'
N—{ch, ) — mm, x' x?
R? a where R! and R? are each, independently, a radiolabelled moiety, e.g. radiolabelled iodine, a methyl group or a phenyl group, and X' and X? are each, independently, a H or
OH.
Preferred radiolabelled molecules are N-(4-hydroxy- 3,5-diiodobenzoyl)-1, 6-hexanediamine and N-(2-hydroxy-3,5- diiodobenzoyl)-1,6-hexanediamine, where either or each of the iodine atoms may be any of the radioisotopes I'¥®, I1'?,
I'** and 1°.
For use in the invention, the bispecific antibody and the cytotoxic agent may be formulated in a kit, e.g. : comprising the two components separately packaged or in separate containers. Each component may be formulated with : a suitable carrier or excipient, examples of which are well known, depending on the route of administration, e.g. oral or intravenous.
The two components will usually be administered sequentially. The effective amount of each may readily be determined by the skilled person, and will depend on typical factors such as the location, severity and spread of the tumour, the condition of the subject etc. It is of course a feature of this invention that the amount of cytotoxic agent that is required will be less than in the absence of the antibody.
Claims (18)
1. A bifunctional antibody having affinity for a tumour and for a therapeutic or diagnostic agent, wherein the agent is an organic molecule.
2. A bifunctional antibody having affinity for a tumour and for a therapeutic agent, wherein the agent is an organic molecule covalently-bound to an enzyme.
3. An antibody according to claim 1 or claim 2, wherein the ligand-affinity is at least 10" 1/mol.
4. An antibody according to any preceding claim, wherein the organic molecule has a molecular weight of less than 1500.
5. An antibody according to any preceding claim, wherein the organic molecule is water-soluble and has a neutral biodistribution in vivo.
6. An antibody according to claim 1, wherein the radio- label is 1'#, 1'*, 1'**, P¥ or I.
7. An antibody according to any preceding claim, wherein the molecule is radiolabelled 4,4-bis(4-hydroxy-3,5- diiodophenyl)pentanoic acid.
8. An antibody according to any of claims 1 to 6, wherein : the molecule is of the formula 1 R' N—{CH, ) —— NH, Rr? an
® WO 00/14119 | PCT/GB99/02938 where R' and R® are, independently a radiolabel, a methyl ) group or a phenyl group, and x! and X? are, independently, H or OH.
9. An antibody according to claim 8, wherein R' and R® : 5 are, independently, a radiolabelled iodine.
10. An antibody according to claim 9,wherein the molecule is radiolabelled N—(4-hydroxy-3,5-dijodobenzoyl)-1,6- hexanediamine or N-(2-hydroxy-3,5-diiodobenzoyl)-1,6- hexanediamine. : - 10
11. An antibody according to claim 1 or claim 2, wherein the molecule is biotin.
12. An antibody according to any preceding claim, wherein . the antibody affinity for the tumour is via a tumour- associated antigen.
13. An antibody according to claim 11, wherein the antigen is carcinoembryonic antigen.
14. An antibody according to any preceding claim, wherein the antibody comprises two single chain Fvs.
15. An antibody according to any preceding claim, wherein the antibody comprises at least the constant regions derived from human immuncglobulin.
16. A radio-labelled compound, wherein the compound is 4,4-bis(4-hydroxy-3,5-diiodophenyl)pentanoic acid, N-(4- hydroxy-3,5-diiodobenzoyl)-1,6~hexanediamine or N-(2- hydroxy-3,5-diiodobenzoyl)-1, 6-hexanediamine.
17. Radiolabelled 4,4~-bis(4-hydroxy-3,5- diiodophenyl)pentanocic acid, radiolabelled N-(4-hydroxy- 3,5-diiodobenzoyl)-1,6-hexanediamine or radiolabelled N-(2- . hydroxy-3,5-diiodobenzoyl)-1,6-hexanediamine, for use in a method of therapy or diagnosis.
18. use of an antibody according to any of claims 1 to 15, for the manufacture of a composition for the treatment of cancer. | i AMENDED SHEET 2002 -02- 25
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| GBGB9819411.1A GB9819411D0 (en) | 1998-09-04 | 1998-09-04 | Antibodies |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| ZA200101574B true ZA200101574B (en) | 2002-02-26 |
Family
ID=10838416
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| ZA200101574A ZA200101574B (en) | 1998-09-04 | 2001-02-26 | Bifunctional antibodies and their use in targeting anti-tumour agents. |
Country Status (20)
| Country | Link |
|---|---|
| EP (1) | EP1107995A2 (en) |
| JP (1) | JP2002524470A (en) |
| KR (1) | KR20010072988A (en) |
| CN (1) | CN1315967A (en) |
| AU (1) | AU5641299A (en) |
| BG (1) | BG105293A (en) |
| BR (1) | BR9913429A (en) |
| CA (1) | CA2341753A1 (en) |
| EA (1) | EA200100311A1 (en) |
| GB (1) | GB9819411D0 (en) |
| HR (1) | HRP20010154A2 (en) |
| HU (1) | HUP0104091A2 (en) |
| ID (1) | ID28873A (en) |
| IL (1) | IL141524A0 (en) |
| MX (1) | MXPA01002349A (en) |
| NO (1) | NO20011102L (en) |
| PL (1) | PL346861A1 (en) |
| TR (2) | TR200103405T2 (en) |
| WO (1) | WO2000014119A2 (en) |
| ZA (1) | ZA200101574B (en) |
Families Citing this family (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN112533952B (en) | 2018-06-01 | 2023-03-07 | 大有华夏生物医药集团有限公司 | Compositions for treating diseases or conditions and uses thereof |
| US20210309745A1 (en) * | 2018-07-26 | 2021-10-07 | Tayu Huaxia Biotech Medical Group Co., Ltd. | Compositions and methods for imaging |
| CN110811820B (en) * | 2019-12-11 | 2022-07-12 | 江西华晨医疗设备有限公司 | Straight rod type flushing and suction electrocoagulation cutter |
Family Cites Families (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US4474893A (en) * | 1981-07-01 | 1984-10-02 | The University of Texas System Cancer Center | Recombinant monoclonal antibodies |
| IL89491A0 (en) * | 1988-11-17 | 1989-09-10 | Hybritech Inc | Bifunctional chimeric antibodies |
| US5217713A (en) * | 1988-12-27 | 1993-06-08 | Takeda Chemical Industries, Ltd. | Cytotoxic bispecific monoclonal antibody, its production and use |
| EP0505566A1 (en) * | 1989-12-15 | 1992-09-30 | Takeda Chemical Industries, Ltd. | Biospecific antibody to cancer cell and enzyme with prodrug-activating characteristics |
| JPH05184383A (en) * | 1990-06-19 | 1993-07-27 | Dainabotsuto Kk | Bispecific antibody |
| US6451980B1 (en) * | 1997-02-26 | 2002-09-17 | Ban-An Khaw | Signal enhancement of bispecific antibody-polymer probe for immunoassay use |
-
1998
- 1998-09-04 GB GBGB9819411.1A patent/GB9819411D0/en not_active Ceased
-
1999
- 1999-09-06 EP EP99943138A patent/EP1107995A2/en not_active Withdrawn
- 1999-09-06 MX MXPA01002349A patent/MXPA01002349A/en not_active Application Discontinuation
- 1999-09-06 JP JP2000568876A patent/JP2002524470A/en active Pending
- 1999-09-06 HU HU0104091A patent/HUP0104091A2/en unknown
- 1999-09-06 ID IDW20010752A patent/ID28873A/en unknown
- 1999-09-06 BR BR9913429-2A patent/BR9913429A/en not_active IP Right Cessation
- 1999-09-06 KR KR1020017002437A patent/KR20010072988A/en not_active Application Discontinuation
- 1999-09-06 CA CA002341753A patent/CA2341753A1/en not_active Abandoned
- 1999-09-06 TR TR2001/03405T patent/TR200103405T2/en unknown
- 1999-09-06 AU AU56412/99A patent/AU5641299A/en not_active Abandoned
- 1999-09-06 EA EA200100311A patent/EA200100311A1/en unknown
- 1999-09-06 IL IL14152499A patent/IL141524A0/en unknown
- 1999-09-06 CN CN99810368A patent/CN1315967A/en active Pending
- 1999-09-06 WO PCT/GB1999/002938 patent/WO2000014119A2/en not_active Application Discontinuation
- 1999-09-06 PL PL99346861A patent/PL346861A1/en not_active Application Discontinuation
- 1999-09-06 TR TR2001/00651T patent/TR200100651T2/en unknown
-
2001
- 2001-02-26 BG BG105293A patent/BG105293A/en unknown
- 2001-02-26 ZA ZA200101574A patent/ZA200101574B/en unknown
- 2001-03-02 HR HR20010154A patent/HRP20010154A2/en not_active Application Discontinuation
- 2001-03-02 NO NO20011102A patent/NO20011102L/en unknown
Also Published As
| Publication number | Publication date |
|---|---|
| MXPA01002349A (en) | 2003-10-15 |
| PL346861A1 (en) | 2002-03-11 |
| HRP20010154A2 (en) | 2002-02-28 |
| BG105293A (en) | 2001-12-29 |
| TR200100651T2 (en) | 2001-07-23 |
| NO20011102L (en) | 2001-03-05 |
| ID28873A (en) | 2001-07-12 |
| WO2000014119A2 (en) | 2000-03-16 |
| EA200100311A1 (en) | 2001-08-27 |
| IL141524A0 (en) | 2002-03-10 |
| GB9819411D0 (en) | 1998-10-28 |
| AU5641299A (en) | 2000-03-27 |
| KR20010072988A (en) | 2001-07-31 |
| BR9913429A (en) | 2001-09-25 |
| CN1315967A (en) | 2001-10-03 |
| TR200103405T2 (en) | 2002-06-21 |
| CA2341753A1 (en) | 2000-03-16 |
| EP1107995A2 (en) | 2001-06-20 |
| NO20011102D0 (en) | 2001-03-02 |
| HUP0104091A2 (en) | 2002-03-28 |
| WO2000014119A3 (en) | 2000-11-30 |
| JP2002524470A (en) | 2002-08-06 |
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