AU594496B2 - The use of monoclonal antibodies for the therapy of tumors - Google Patents

The use of monoclonal antibodies for the therapy of tumors Download PDF

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Publication number
AU594496B2
AU594496B2 AU77663/87A AU7766387A AU594496B2 AU 594496 B2 AU594496 B2 AU 594496B2 AU 77663/87 A AU77663/87 A AU 77663/87A AU 7766387 A AU7766387 A AU 7766387A AU 594496 B2 AU594496 B2 AU 594496B2
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growth factor
monoclonal antibody
carcinoma
therapy
pancreatic
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AU77663/87A
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AU7766387A (en
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Klaus Bosslet
Hans Ulrich Schorlemmer
Hans-Harald Sedlacek
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Siemens Healthcare Diagnostics GmbH Germany
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Behringwerke AG
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    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • C07K16/303—Liver or Pancreas
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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  • Life Sciences & Earth Sciences (AREA)
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  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Cell Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Gastroenterology & Hepatology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Biochemistry (AREA)
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  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Microbiology (AREA)
  • Mycology (AREA)
  • Epidemiology (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
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Abstract

The use of a monoclonal antibody, of one of its non-Fc fragments or another ligand, which have the properties of blocking the pinocytosis of colloidal gold, the production of superoxide anions or the release of enzymes, particularly of neutral proteases, very particularly collagenase or elastase, of growth factors, epidermal growth factor, platelet-derived growth factor, colony-stimulating factor, erythropoietin, fibroblast growth factor, tumour angiogenesis factor or transforming growth factor from pancreatic tumour cells, for the therapy of tumours is described.

Description

il q(rli 7 COMvMONWEALTH OF AUISTRALIA5 9 l r- PATENTS ACT 1952-69 COMPLETE SPECIFICATION
(ORIGINAL)
Class I t. Class Application Number: Lodged: Com~plete Specification Lodged; Accepted: Published: 33 3 Briority: ~Relaed Art: Trhis docunent contains the Eaundmeiits mhade under &e ction 49 and Is correct- for Name of Applicant: 0 p.
Address of Applicant: 0 Actual Inventor: Address for Service: BEI-RINGWERKE AKTIENGESEL 4
LSCHAFT
D-3550 Marburg, Federal Republic of Germany.
KLAUS BOSSLET, H-ANS ULRIECH SCi-ORLEMMER and HANS HARALD SWDLACEK.
EDWD. WATE RS SONS, 50 QUEFN STREET, MELBOURNE, AUSTRALIA, 3000.
4' complete Specification for the nVdentiofl entitled,, "THE USE OF MONOCLONAL ANTIBODIES FOR THE THERAPY OF TUMORSI" T he following statement a full description of this Invention, Including the best method of performing It known to 11 US la BEHRINGWERKE AKTIENGESELLSCHAFT 86/B 028 Ma 596 Dr. Ha/Bn/Li.
I The use of monoclonal antibodies for the therapy of tumors The invention relates to the use of monoclonal antibodies (MAb) or other ligands which have the property of binding to pancreatic carcinoma cells and of blocking at least one of the following cellular functions: pinocytosis of colloidal gold, production of superoxide anion or release of enzymes, especially of neutral proteases, very especially collagenase or elastase, of growth factors, epidermal growth factor, platelet-derived growth factor, colony- 4 stimulating factor, erythropoietin, fibroblast growth factor, tumor angiogenesis factor or transforming growth factor, for tumor therapy.
Processes suitable for the preparation of monoclonal antii bodies of these types are described in European Patent A-0 160 897, in German Offenlegungsschrift 33 29 184 and in German Patent Application 35 31 301 (filed on Sept. 2, S 1985). The molecules designated as ligands are not mono- 0 clonal antibodies but they also bind to pancreatic carcino.ma cells and inhibit their cellular functions, for 'e't20 example certain hormones.
It has been found, surprisingly, that human pancreatic carcinoma cell lines are able to secrete lysosomal enzymes, pinocytose colloidal gold and generate superoxide anion, and that these cellular functions can be blocked by binding monoclonal antibodies, in particular 494/32, 495/36, 227/18 or 227/19, to the pancreatic carcinoma cells. MAbs 494/32 and 495/36 are described in the cited patent appli- cation, whereas the others are described in the cited Offenlegungsschrift. In these citations they are designated as follows: 227/18 as AK 2 (Table on page 8) and 227/19 as AK 16.
One consequence of the attachment of such MAbs, which is followed by blocking of the said cellular functions, is the 2 regression of progressively growing pancreatic carcinomas in patients.
These cellular functions of pancreatic carcinoma cells include the release of, in particular, neutral proteases, very particularly collagenase or elastase, of growth factors, epidermal growth factor, platelet-derived growth factor, colony-stimulating factor, erythropoietin, fibroblast growth factor, tumor angiogenesis factor or transforming growth factor.
Monoclonal antibodies (Mab) which have the property of binding to pancreatic carcinoma cells and of blocking o o o0 physiological functions, preferably the pinocytosis of 15 15 colloidal gold, the production of superoxide anion or the 0 0 release of enzymes, especially of neutral proteases, very 0a 00 o 00 especially collagenase or elastase, of growth factors, 0o epidermal growth factor, platelet-derived growth factor, colony stimulating factor, erythropoietin, fibroblast growth factor, tumor angiogenesis factor or transforming growth factor, are accordingly suitable for the therapy of tumors t whose cells exhibit these cellular functions. Equally Ssuitable are binding fragments of a MAb of this type, C Cc except the Fc fragment, as well as other ligands, that is to say molecules with the property of binding to pancreatic carcinoma cells and of blocking the said functions.
OC
c Apart from p'ancreatic carcinomas, examples of tumor cells with relevant secretory properties are carcinomas of the breast, ovarian carcinomas and adenocarcinomas of the lungs.
Hence the invention relates to the use of a monoclonal antibody or of one of its non-Fc fragments or of another ligand, each of which has the property of blocking the following cellular functions of a tumor cell: the pinocytosis of colloidal gold, the production of superoxide anion or the release of enzymes, especially of neutral proteases, very especially collagenase or elastase, of growth factors, r urr- 3 epidermal growth factor, platelet-derived growth factor, colony-stimulating factor, erythropoietin, fibroblast growth factor, tumor angiogenesis factor or transforming growth factor from pancreatic tumor cells, for the therapy of tumors.
Tumors which can be treated with such MAbs or other ligands are, preferably, pancreatic carcinomas, carcinomas of the breast, ovarian carcinomas or adenocarcinomas of the lungs, in particular pancreatic carcinomas.
0 a a o os o 15 o o o o o0 0 00 It is possible to use pancreatic carcinoma cell lines, preferably the PANC-1 line (Int. J. Cancer (1975) 741; ATCC CRL 1469), for testing whether the MAbs or Ligands bind to pancreatic carcinoma cells.
o a 00 0 t* i C tC c r r To select MAbs or ligands which can be used in the manner according to the invention, the inhibition by the MAbs or ligands of the chemiluminescence of cells of a cell line 20 of this type is determined. The determination of the chemiluminescence of cells is a method for detecting the generation of superoxide anion by a cell and for determining the amount thereof.
For this purpose, the tumor cell line is cultured in Dulbecco's minimal essential medium (DMEM) which contains 100 ml/l fetal calf serum and 1 mmol/l glutamine (DMEM- FCS-GLN). This entails the cell line in the confluent state being treated with 2g/L trypsin and 0.2 g/L EDTA in Puck's saline at 37°C for 1 minute and, after washing, being transferred in the ratio 1:20 into DMEM-FCS-GLN.
The isola'ted cells are left to adhere in DMEM in a roundbottomed polystyrene tube, at a cell count of 106 cells, for 4 hours. After having been washed in DMEM three times, 100 up of DMEM are added and the cell suspensions are placed in the counting chamber of a Biolumate (LB 95 05 Berthold Co., Wildbad, FRG). 50 4l of luminol (100 ug/ml) and 100 il of a stimulus (50 pg/ml zymosan or 100 Ug/ml of an immune complex or, to the control, 100 pL of PBS) are 7 -j 4 added to the contents of the tube, and the Light emission is measured (Apple II computer with MX-82 FIT Epson dot matrix printer). To determine the inhibition by a MAb, 100 pl of a solution of the MAb are added and the mixture is incubated for 15 minutes (final concentration 10 pg/ml).
The MAbs 494/32, 495/36, 227/18, 431/31 and the others described in German Offenlegungsschrift 33 29 184, 227/12 (AK 12) and 227/19 (AK 16) were used, by way of example, in this or the following assay systems, and their binding to the corresponding tumor cell lines were measured in the indirect immunofluorescence assay of Terasaki (Cancer de- :o°0o tection and prevention (1983), 6, 181).
0 0 I 15 Table 1, which follows, shows the results.
0 0 a Table 1 04 o 000 MAb Binding Inhibition of chemiluminescence 20 assay Stimulus 0O Soo (Terasaki) PBS Zymosan Immune complex 0 0 (control) 0 *0 0 *0 227/12 negative 0 7 3 431/31 negative 0 8 0 494/32 positive 6 59 37 0 227/18 positive 21 54 66 227/19 positive 17 42 48 It is evident from the table that the MAbs which do not 4 bind to the tumor cell membrane do not inhibit the chemiluminescence, whereas those which bind do inhibit it. i
I
This also applies to other MAbs which are suitable as therapeutic agents for tumors.
The procedure for testing the ability of a MAb to inhibit pinocytosis and enzyme secretion was as follows: t 6 3 x 10 tumor cells which have been obtained as described above and cultured in 3.5 cm Petri dishes are incubated for 24 hours with the stimuli (zymosan or an immune complex or PBS (control) and, where appropriate, together with 10 ig of MAb per ml), and the ability of the MAbs to inhibit the release of enzymes by the cells is tested as stated in the citations given (B-glucuronidase, J. biol. Chem. (1946) 166, 757; B-galactosidase: Biochem. J. (1959) 71, 318; lactate dehydrogenase: Methoden der enzymatischen Analyse (Methods of enzyme analysis) Verlag Chemie, Weinheim/ Bergstrasse, Federal Republic of Germany, page 533 (1970); Pinocytosis activity: Biochem. Biophys. Res. Comm. (1973) 9 ,0 52, 627).
0 o 15 Table 2 likewise shows that MAbs which bind to the PANC-1 0 cell also inhibit its enzyme release, whereas others do 04 0 to not cause this.
0O 0 0o Table 2 U0 0 0. Enzyme release inhibition) 0 MAb PBS Zym IC 494/32 21 42 34 495/36 26 86 227/18 2 52 52 4 00 o 227/19 0 54 51 431/31 4 7 3 227/12 5 0 0 Table 3 shows the ability of monoclonal antibodies to inhibit the basal pinocytosis activity of pancreatic tumor cells after binding to the tumor cell membrane. Those which do not bind do not inhibit the pinocytosis of 198 Au.
The results obtained with the F(ab') 2 fragment of MAb 494/32 were identical to those with the intact immunoglobulin.
-T -L3Y I- 6 -6 STable 3 MAb Inhibition of uptake of 198Au 494/32 42 495/36 53 227/18 61 227/19 431/31 227/12 4 MAbs or their non-Fc fragments or othej Ligands which are *°o 0 able to inhibit all or some of the pancreatic carcinoma s a ceLL functions indicated above can be used for the therapy a of tumors, in particular of pancreatic carcinomas.
04 SBOo Clinical data after i.v. administration of MAb 494/32 so o (5x at intervals of one day to a total dose of 210 mg) show that, with progressive pancreatic carcinoma, thjs MAb causes, after palliative operation, arrest of the disease in 4 of 6 cases (confirmed by computerized tomography) and Ii t brings about a subjective improvement in the general condition of the patients.
A Pharmaceutical suitable for the therapy of tumors contains a MAb or ligand having the properties described in the form of a solution, or in frozen or dried form. One daily dose is in the range 20 to 500 mg pe' 70 mg of bodyweight. The agent is administered parenterally, preferabLy Sf infused. An effective amount is administered to the patient in a period of from 1 minute to 3 h. The agent is given in time intervals of from one day up to several months.

Claims (6)

1. A method of healment of tumors comprising administering to a patient suffering therefrom a monoclonal antibody or one of its non-Fc fragments or a ligand selected by determining the chemiluminescence of cells of a carcinoma cell line each of which has at least one of the following properties: blocking the pinocytosis of colloidal gold, the production of superoxide anion or the release of enzymes, especially of neutral proteases, very especially collagenase or elastase, of epidermal growth factor, platelet-derived growth factor, colony-stimulating factor, erythropoietin, fibroblast growth factor, tumor angio-genesis factor or transforming growth factor of pancreatic tumor cells. I 0o
2. The use of a monoclonal antibody as claimed in claim 1 for the therapy of a pancreatic carcinoma, carcinoma 0o o t° of the breast, ovarian carcinoma or adenocarcinoma of the P OD o lungs. o a 6 00 Po
3. The use of a monoclonal antibody as claimed in o. claim 1 for the therapy of a pancreatic carcinoma.
4. The use of a monoclonal antibody as claimed in claim 1 and which is BW 494/32. t
5. The use of the monoclonal antibody BW 494/32 for the therapy of a pancreatic carcinoma, of a carcinoma of the breast, of an ovarian carcinoma or of an adenocarcinoma of *tt the lungs.
6. The use of the monoclonal antibody BW 494/32 for the therapy of a pancreatic carcinoma. The use of a monoclonal antibody as claimed in ,~i r 8 claim 1 in a process for the preparation of a therapeutic agent for tumor. DATED this 13th day of December, 1989. BEHRINGWERKE AKTIENGESELLSCHAFT '~o o c 0 o 0 o I a. p p ~Qb t~ ,pt WATERMARK PATENT TRADEMARK ATTORNEYS, ,290 BURWOOD ROAD, HAWTHORN, VICTORIA, AUSTRALIA. DBM:KS:BB(7.7) .51
AU77663/87A 1986-08-30 1987-08-28 The use of monoclonal antibodies for the therapy of tumors Ceased AU594496B2 (en)

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DE19863629640 DE3629640A1 (en) 1986-08-30 1986-08-30 USE OF MONOCLONAL ANTIBODIES FOR THE TREATMENT OF TUMORS
DE3629640 1986-08-30

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EP (1) EP0258817B1 (en)
JP (1) JP2624968B2 (en)
KR (1) KR880002543A (en)
AT (1) ATE104679T1 (en)
AU (1) AU594496B2 (en)
DE (2) DE3629640A1 (en)
DK (1) DK452587A (en)
PT (1) PT85599B (en)
ZA (1) ZA876438B (en)

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GB9106678D0 (en) * 1991-03-28 1991-05-15 Ferguson Mark W J Wound healing
US7507705B2 (en) 1997-10-02 2009-03-24 MAX-PLANCK-Gesellschaft zur Förderung der Wissenschaften e.V. Methods for the modulation of neovascularization and/or the growth of collateral arteries and/or other arteries from preexisting arteriolar connections

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0160897A2 (en) * 1984-05-07 1985-11-13 BEHRINGWERKE Aktiengesellschaft Monoclonal antibodies, process for preparing them and their use
EP0213581A2 (en) * 1985-09-02 1987-03-11 BEHRINGWERKE Aktiengesellschaft Monoclonal antibodies against tumour-associated glycoproteins, process for their preparation and their use

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE3329184A1 (en) * 1983-08-12 1985-02-21 Behringwerke Ag, 3550 Marburg MONOCLONAL ANTIBODIES WITH SPECIFICITY FOR MEMBRANE-ASSOCIATED ANTIGENS
NZ210867A (en) * 1984-01-31 1989-01-06 Litton Bionetics Inc Tumour-specific monoclonal antibodies, production thereof and use
CA1339798C (en) * 1985-02-01 1998-04-07 Alan N. Houghton Method for treatment of neuroectodermal malignancies and epithelial carcinomas in humans

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0160897A2 (en) * 1984-05-07 1985-11-13 BEHRINGWERKE Aktiengesellschaft Monoclonal antibodies, process for preparing them and their use
EP0213581A2 (en) * 1985-09-02 1987-03-11 BEHRINGWERKE Aktiengesellschaft Monoclonal antibodies against tumour-associated glycoproteins, process for their preparation and their use

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ZA876438B (en) 1988-04-27
EP0258817A3 (en) 1988-06-15
JPS6372630A (en) 1988-04-02
DK452587A (en) 1988-03-01
AU7766387A (en) 1988-03-03
PT85599A (en) 1987-09-01
EP0258817A2 (en) 1988-03-09
DK452587D0 (en) 1987-08-28
KR880002543A (en) 1988-05-09
EP0258817B1 (en) 1994-04-20
JP2624968B2 (en) 1997-06-25
DE3789643D1 (en) 1994-05-26
ATE104679T1 (en) 1994-05-15
DE3629640A1 (en) 1988-03-03
PT85599B (en) 1990-05-31

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