EP0452315A1 - Methode de traitement de la leucemie myeloide - Google Patents

Methode de traitement de la leucemie myeloide

Info

Publication number
EP0452315A1
EP0452315A1 EP89907439A EP89907439A EP0452315A1 EP 0452315 A1 EP0452315 A1 EP 0452315A1 EP 89907439 A EP89907439 A EP 89907439A EP 89907439 A EP89907439 A EP 89907439A EP 0452315 A1 EP0452315 A1 EP 0452315A1
Authority
EP
European Patent Office
Prior art keywords
csf
human
antagonist
cells
pgs
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP89907439A
Other languages
German (de)
English (en)
Inventor
John S. Abrams
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Schering Biotech Corp
Original Assignee
Schering Biotech Corp
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering Biotech Corp filed Critical Schering Biotech Corp
Publication of EP0452315A1 publication Critical patent/EP0452315A1/fr
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/18—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/24—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/243—Colony Stimulating Factors
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A61P35/02—Antineoplastic agents specific for leukemia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the invention relates generally to a method for treating diseases caused or exacerbated by excessive production of granulocyte-macrophage colony stimulating factor (GM-CSF) , and more particularly to a method of treating yeloid leukemias.
  • GM-CSF granulocyte-macrophage colony stimulating factor
  • BACKGROUND Circulating blood cells are constantly replaced by newly developed cells.
  • Replacement blood cells are formed in a process termed hematopoiesis in which at least eight mature blood cell types within two major lineages are produced: (1) myeloid lineages, which include red blood cells (erythrocytes) , macrophages (monocytes) , eosinophilic granulocytes, megakaryocytes (platelets), neutrophilic granulocytes, basophilic granulocytes (mast cells) ; and (2) lymphoid lineages, which include T lymphocytes, and B lymphocytes: Burgess and Nicola, Growth Factors and Stem Cells (Academic Press, New York, 1983) .
  • myeloid lineages which include red blood cells (erythrocytes) , macrophages (monocytes) , eosinophilic granulocytes, megakaryocytes (platelets), neutrophilic granulocytes, basophilic gran
  • CSFs colony stimulating factors
  • CSFs The role of CSFs in hematopoiesis is the subject of many recent reviews, e.g. Metcalf, The Hemopoietic Colony Stimulating Factors (Elsevier, New York, 1984), Metcalf, Science, Vol. 1229, pgs. 16-22 (1985), Nicola et al. , Immunology Today, Vol. 5, pgs. 76- 80 (1984), hetton et al. , TIBS, Vol. 11, pgs. 207-211 (1986), Clark and Kamen, Science, Vol. 236, pgs. 1229- 1237 (1987) , and Sachs, Science, Vol. 238, pgs. 1374-1379 (1987) .
  • CSFs are also believed to play a role in the development and progression of myeloid leukemias.
  • Myeloid leukemias are clonal neoplasms of granulocyte- macrophage precursor cells, which fall into two major groups - chronic myeloid leukemia (CML) and acute myeloid leukemia (AML) .
  • CML chronic myeloid leukemia
  • AML acute myeloid leukemia
  • AML is characterized by an accumulation of immature granulocyte-monocyte blast cells with often little or no evidence of maturing granulocyte-monocyte cells.
  • the disease primarily involves the bone marrow, and spleen enlargement usually is only moderate.
  • Total blood nucleated cells may or may not be elevated but there is a high proportion of immature blast cells associated with relatively few mature cells.
  • leukemia both forms are driven by abnormal production of, or responsiveness to, colony stimulating factors, particularly GM-CSF.
  • colony stimulating factors particularly GM-CSF.
  • leukemi ⁇ cells from some AML patients are capable of autonomous in vitro proliferation because they express GM-CSF constitutively, and that such autonomous proliferation can be inhibited by the addition of GM-CSF neutralizing antiserum; Young et al. , Blood, Vol. 68, pgs. 1178-1181 (1986).
  • the present invention relates to the treatment of myeloid leukemias, in particular AML, by blocking the ability of GM-CSF to stimulate cell growth.
  • Such blocking could be carried out by the use of monoclonal antibodies specific for human GM-CSF. Accordingly, the availability of monoclonal antibodies capable of blocking GM-CSF activity could give rise to a new approach to treating myeloid leukemias.
  • the invention therefore provides a method of reducing effective GM-CSF concentrations by administering an effective amount of an antagonist to human GM-CSF. More particularly, the invention includes a method for treating myeloid leukemias by administering an effective amount of an antagonist to human GM-CSF.
  • the antagonists to GM-CSF are monoclonal antibodies capable of blocking the biological activity of GM-CSF, fragments thereof, or binding compositions derived therefrom by standard techniques.
  • antagonists to GM-CSF are derived from the monoclonal antibodies, or the genes thereof, produced by hybridomas BVD2-5A2.4, BVD2-23B6.4, and BVD-21C11.3.
  • the invention is based on the discovery of monoclonal antibodies capable of blocking the biological activity of human GM-CSF, and the discovery that certain myeloid leukemias are caused by autocrine secretion of GM-CSF.
  • the method of the invention comprises administering to a person an effective, or disease- ameliorating amount, of an antagonist to human GM-CSF.
  • the antagonists of the invention are derived from antibodies capable of blocking the biological activity of human GM-CSF.
  • Antibodies comprise an assembly of polypeptide chains linked together by disulfide bridges. Two major polypeptide chains, referred to as the light chain and the heavy chain, make up all major structural classes (isotypes) of antibody. Both heavy chains and light chains are further divided into subregions referred to as variable regions and constant regions. Heavy chains comprise a single variable region and three different constant regions, and light chains comprise a single variable region (different from that of the heavy chain) and a single constant region (different from those of the heavy chain) . The variable regions of the heavy chain and light chain are responsible for the antibody's binding specificity.
  • heavy chain variable region means a polypeptide (1) which is from 110 to 125 amino acids in length, and (2) whose amino acid sequence corresponds to that of a heavy chain of a monoclonal antibody of the invention, starting from the heavy chain's N-terminal amino acid.
  • light chain variable region means a polypeptide (l) which is from 95 to 115 amino acids in length, and (2) whose amino acid sequence corresponds to that of a light chain of a monoclonal antibody of the invention, starting from the light chain's N-terminal amino acid.
  • monoclonal antibody refers to homogenous populations of immunoglobulms which are capable of specifically binding to, and blocking the biological activity of, human GM-CSF.
  • binding composition means a composition comprising two polypeptide chains (1) which, when operationally associated, assume a conformation having high binding affinity for human GM- CSF, and (2) which are derived from a hybridoma producing monoclonal antibodies specific for, and capable of blocking the biological activity of, human GM-CSF.
  • operationally associated is meant to indicate that the two polypeptide chains can be positioned relative to one another for binding by a variety of means, including association in a native antibody fragment, such as Fab or Fv, or by way of genetically engineered cysteine-containing peptide linkers at the carboxyl termini.
  • the two polypeptide chains correspond to the light-chain variable region and heavy-chain variable region of a monoclonal antibody specific for human GM-CSF.
  • antagonists of the invention are derived from monoclonal antibodies capable of blocking the biological activity of human GM-CSF.
  • monoclonal antibodies are obtained by a double screening procedure. The first, by an indirect enzyme-linked immunoabsorbent assay (ELISA) or an immunometric ELISA screen, selects for antibodies specific for human GM- CSF. From this set, a second screen is used to assess the antibody's ability to block, or neutralize, the biological activity of human GM-CSF.
  • ELISA enzyme-linked immunoabsorbent assay
  • an immunometric ELISA screen selects for antibodies specific for human GM- CSF. From this set, a second screen is used to assess the antibody's ability to block, or neutralize, the biological activity of human GM-CSF.
  • Several biological assays are available for GM-CSF. In particular, bone marrow or umbilical cord blood assays in a semi-solid medium can be used, e.g.
  • the GM-CSF-dependent cell line KG-1 can be used, e.g. in such assays as are disclosed by Koeffler et al., Science, Vol. 200, pgs. 1153-1154 (1978), and by Lusis et al., Proc. Natl. Acad. Sci., Vol. 77, pgs. 5346-5350 (1980); the KG-1 cell line is available through the ATCC under accession number CCL 246.
  • Bone marrow and cord blood assays are carried out as follows. Bone marrow cells collected from patients with nonhematologic disease are layered over Ficoll (type 400, Sigma Chemical Co., St. Louis, MO) and centrifuged (600 x g, 20 min) , and the cells at the interface removed. These cells are washed twice in Iscove's Modified Dulbecco's Medium containing 10% fetal calf serum (FCS) and resuspended in the same medium, and the adherent cells removed by adherence to plastic Petri dishes (adherent cells are frequently GM-CSF producing cells; see Metcalf (cited above)).
  • Ficoll type 400, Sigma Chemical Co., St. Louis, MO
  • FCS fetal calf serum
  • the nonadherent cells are added at 10 5 cells/ml to Iscove's Medium containing 20% FCS, 50 ⁇ 2-mercaptoethanol, 0.9% methylcellulose and various concentrations of either supernatants known to contain colony stimulating activity a__ test supernatants.
  • One ml aliquots are plated in 35 mm petri dishes and cultured at 37°C in a fully humidified atmosphere of 6% C0 2 in air.
  • 3 days after the initiation of the culture 1 unit of erythropoietin is added to each plate.
  • Granulocyte-macrophage colonies and erythroid bursts are scored at 10-14 days using an inverted microscope.
  • Cord blood cells collected in heparin are spun at 600 x g for 6 min.
  • the white blood cells at the interface between the plasma and red blood cell peak are transferred to a tube containing 0.17 N ammonium chloride and 6% FCS.
  • the suspension is underlaid with 4 ml FCS and centrifuged for 6 minutes at 600 x g.
  • the cell pellet is washed with Dulbecco's phosphate buffered saline and put through the Ficoll and plastic adherence steps as described above for bone marrow cells.
  • the low density nonadherent cells are collected and placed at 10 5 cells/culture in the semi- solid culture medium as described above.
  • the cellular composition is determined after applying the individual colonies to glass slides and staining with Wright- Gei sa. Eosinophils are determined by staining with Luxol Fast Blue, e.g. Johnson, G. and Metcalf, D., Exp. He atol. , Vol. 8, pgs. 549-561 (1980).
  • Hybridomas of the invention are produced by well-known techniques. Usually, an immortalizing cell line is fused with a B-lymphocyte that produces the desired antibody. Alternatively, non-fusion techniques for generating immortal antibody-producing cell lines are possible, and come within the purview of the present invention; e.g. virally induced transformation: Casali et al. , "Human Monoclonals from Antigen-Specific Selection of B Lymphocytes and Transformation by EBV," Science, Vol. 234, pgs. 476-479 (1986). Immortalizing cell lines are usually transformed mammalian cells, particularly myeloma cells of rodent, bovine, or human origin. Most frequently, rat or mouse myeloma cell lines are employed as a matter of convenience and availability.
  • lymphocytes are well known. Generally, peripheral blood lymphocytes (PBLs) are used if cells of human origin are desired, whereas spleen cells or lymph node cells are used if non- human mammalian sources are desired. A host mammal is injected with repeated dosages of the purified antigen, and the mammal is permitted to generate the desired antibody-producing cells before these are harvested for fusion with the immortalizing cell line. Techniques for fusion are also well known in the art, and in general involve mixing the cells with a fusing agent, such as polyethylene glycol. Hybridomas are selected by standard procedures, such as HAT selection.
  • those secreting the desired antibody are selected by assaying their culture medium by standard immunoassays, such as Western blotting, ELISA, RIA, or the like.
  • Antibodies are recovered from the medium using standard protein purification techniques, e.g. Tijssen, Practice and Theory of Enzyme Immunoassays (Elsevier, Amsterdam, 1985) .
  • Many references are available for guidance in applying any of the above techniques: e.g.
  • Such compounds and compositions of the invention can be used to construct bi-specific antibodies by known techniques, e.g., by further fusions of hybridomas (i.e. to form so-called quadromas) , Reading, U.S. Patent 4,474,493, or by chemical reassociation of half molecules, Brennan et al., Science, Vol. 229, pgs. 81-83 (1985) .
  • Hybridomas and monoclonal antibodies of the invention are produced against either glycosylated or unglycosylated versions of recombmantly produced mature human GM-CSF.
  • unglycosylated versions of human GM-CSF are produced in E. coli, and glycosylated versions are produced in mammalian cell hosts, e.g. CV1 or COS monkey cells, mouse L cells, or the like.
  • Recombinantly produced mature human GM-CSF is produced by introducing an expression vector into a host cell using standard protocols: e.g. Maniatis et al. , Molecular Cloning: A Laboratory Manual (Cold Spring Harbor Laboratory, New York, 1982) ; Okayama and Berg, Mol. Cell. Biol.
  • Antibodies and antibody fragments characteristic of hybridomas of the invention can also be produced by recombinant means by extracting messenger RNA, constructing a cDNA library, and selecting clones which encode segments of the antibody molecule: e.g. Wall et al., Nucleic Acids Research, Vol. 5, pgs. 3113- 3128 (1978); Zakut et al., Nucleic Acids Research, Vol. 8, pgs. 3591-3601 (1980); Cabilly et al., Proc. Natl. Acad. Sci., Vol. 81, pgs. 3273-3277 (1984); Boss et al., Nucleic Acids Research, Vol. 12, pgs.
  • Antagonists of the invention are administered as a pharmaceutical composition for treating myeloid leukemias.
  • Such compositions contain an effective amount of at least one of the monoclonal antibodies of the invention, or fragments thereof, in a pharmaceutical carrier.
  • a pharmaceutical carrier can be any compatible, non-toxic substance suitable for delivering the compositions of the invention to a patient.
  • compositions useful for parenteral administration of such drugs are well known, e.g. Remington 's Pharmaceu ica1 Science, 15th Ed. (Mack Publishing Company, Easton, PA 1980) .
  • compositions of the invention may be introduced into a patient's body by an implantable drug delivery system, e.g. Urquhart et al., Ann. Rev. Pharmacol. Toxicol. , Vol. 24, pgs. 199-236 (1984).
  • the antibodies or fragments When administered parenterally the antibodies or fragments will be formulated in a unit dosage injectable form (solution, suspension, emulsion) in association with a pharmaceutically acceptable pharmaceutical carrier.
  • a pharmaceutically acceptable pharmaceutical carrier Such carriers are inherently nontoxic and nontherapeutic. Examples of such carriers are normal saline, Ringer's solution, dextrose solution, and Hank's solution. Nonaqueous carriers such as fixed oils and ethyl oleate may also be used. A preferred carrier is 5% dextrose/saline.
  • the carrier may contain minor amounts of additives such as substances that enhance isotonicity and chemical stability, e.g., buffers and preservatives.
  • the antibody is preferably formulated in purified form substantially free of aggregates and other proteins at concentrations of about 5 to 30 mg/ml, preferably 10 to 20 mg/ml.
  • an administration regimen for an antagonist depends on several factors, including the serum turnover rate of the antagonist, the circulating, extracellular level of GM-CSF associated with the leukemia, the immunogenicity of the antagonist, the accessibility of the target GM-CSF (e.g. if non-serum GM- CSF is to be blocked) , the relative affinity of GM-CSF to its receptor(s) versus GM-CSF to the antagonist, and the like.
  • an administration regimen maximizes the amount of antagonist delivered to the patient consistent with an acceptable level of side effects. Accordingly, the amount of antagonist delivered depends in part on the particular antagonist and the severity of the disease being treated. Guidance in selecting appropriate doses is found in the literature on therapeutic uses of antibodies; e.g.
  • the antagonist comprises monoclonal antibodies or Fab-sized fragments thereof (including binding compositions)
  • the dose is in the range of about 1-20 mg/kg per day. More preferably the dose is in the range of abut 1-10 mg/kg per day.
  • the immunogenicity of the antibodies or fragments can be reduced by appropriate derivatization, e.g. with polyethylene glycol, or the like; Beauchamp et al., Anal. Biochem. , Vol. 131, pgs. 25-33 (1983); and Abuchowski et al. , J. Biol. Chem. , Vol. 252, pgs. 3578-3581 and 3582-3586 (1977).
  • Applicants have deposited hybridomas BVD-5A2.4, BVD2-23B6.4, and BVD2-21C11.3 with the American Type Culture Collection, Rockville, Maryland, USA (ATCC) , under accession numbers HB9567, HB9568, and HB9569, respectively. These deposits were made under conditions as provided under ATCC's Agreement for Culture Deposit for Patent Purposes, which assures that the deposits will be made available to the US Commissioner of Patents and Trademarks pursuant to 35 U.S.C. 122 and 37 C.F.R. 1.14, and will be made available to the public upon issue of a U.S. patent, which requires that the deposits be maintained. Availability of the deposited strains is not to be construed as a license to practise the invention in contravention of the rights granted under the authority of any government in accordance with its patent laws.
  • the deposit has been modified to conform to the requirements of the Budapest Treaty on the Deposit of Microorganisms.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Veterinary Medicine (AREA)
  • Immunology (AREA)
  • Oncology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • General Chemical & Material Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Hematology (AREA)
  • Public Health (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicines Containing Antibodies Or Antigens For Use As Internal Diagnostic Agents (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

Une méthode de traitement de la leucemie myéloïde consiste à administrer à une personne une quantité efficace d'un antagoniste contre le GM-CSF. De préférence, l'antagoniste est un anticorps monoclonal de blocage spécifique contre le GM-CSF humain, ou un fragment ou une composition de liaison dérivé de celui-ci.
EP89907439A 1988-05-31 1989-05-26 Methode de traitement de la leucemie myeloide Pending EP0452315A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US20075588A 1988-05-31 1988-05-31
US200755 2002-07-24

Publications (1)

Publication Number Publication Date
EP0452315A1 true EP0452315A1 (fr) 1991-10-23

Family

ID=22743047

Family Applications (2)

Application Number Title Priority Date Filing Date
EP89907439A Pending EP0452315A1 (fr) 1988-05-31 1989-05-26 Methode de traitement de la leucemie myeloide
EP89305368A Withdrawn EP0347057A1 (fr) 1988-05-31 1989-05-26 Traitement des leucemies myeloides

Family Applications After (1)

Application Number Title Priority Date Filing Date
EP89305368A Withdrawn EP0347057A1 (fr) 1988-05-31 1989-05-26 Traitement des leucemies myeloides

Country Status (4)

Country Link
EP (2) EP0452315A1 (fr)
JP (1) JPH03502582A (fr)
AU (1) AU3834589A (fr)
WO (1) WO1989011864A1 (fr)

Families Citing this family (8)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9015908D0 (en) * 1990-07-19 1990-09-05 Celltech Ltd Multivalent immunoglobulin
CA2060741A1 (fr) * 1991-02-11 1992-08-12 Robert S. Greenfield Oligopeptides inhibant le gm-csf
CA2060699A1 (fr) * 1991-02-11 1992-08-12 Isia Bursuker Oligopeptides inhibtant le gm-csf
AU703052B2 (en) * 1995-06-23 1999-03-11 Bresagen Limited Haemopoietic growth factor antagonists and uses therefor
AUPN378095A0 (en) * 1995-06-23 1995-07-20 Bresagen Limited Haemopoietic growth factor antagonists and uses therefor
DE102005022319A1 (de) * 2005-05-10 2006-11-23 Symbiotec Gesellschaft Zur Forschung Und Entwicklung Auf Dem Gebiet Der Biotechnologie Mbh Verwendung von Histonen zu therapeutischen Zwecken
CN104072613A (zh) * 2007-11-13 2014-10-01 Evec股份有限公司 与hGM-CSF结合的单克隆抗体及包含它的药物组合物
WO2023110942A1 (fr) * 2021-12-14 2023-06-22 Charité-Universitätsmedizin Berlin Prévention de guérison d'une fracture altérée

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
UA39161C2 (uk) * 1984-07-06 2001-06-15 Новартіс Аг Рекомбінантний білок gm-csf для збільшення продукції гранулоцитів і макрофагів у пацієнтів, вектор і кднк, що його кодують
NZ218336A (en) * 1985-12-09 1991-08-27 Kirin Amgen Inc Monoclonal antibodies to human pluripotent granulocyte colony stimulating factor (hpg-csf)
GB8624899D0 (en) * 1986-10-17 1986-11-19 Sandoz Ltd Monoclonal antibodies

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO8911864A1 *

Also Published As

Publication number Publication date
AU3834589A (en) 1990-01-05
JPH03502582A (ja) 1991-06-13
EP0347057A1 (fr) 1989-12-20
WO1989011864A1 (fr) 1989-12-14

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