Modified forms of granulocyte macrophage-colony stimulating fact

Details Modified forms of granulocyte macrophage-colony stimulating fact Modified forms of granulocyte macrophage-colony stimulating fact

1996-04-08

1999-08-17

Mertz, Prema

Drug, bio-affecting and body treating compositions

Lymphokine

530351, 435 695, 435 712, 435471, 435325, 4352523, 4353201, A61K 3819, C07K 14535

Patent

active

059390638

DESCRIPTION:

BRIEF SUMMARY
The present invention relates to modified and variant forms of haemopoietic growth factors capable of acting as antagonists to the corresponding native haemopoietic growth factors and their use in ameliorating aberrant effects caused by the native molecules.
Bibliographic details of the publications numerically referred to in this specification are collected at the end of the description. Sequence Identity Numbers (SEQ ID NOs.) for the nucleotide and amino acid sequences referred to in the specification are defined following the bibliography.
Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated element or integer or group of elements or integers but not the exclusion of any other element or integer or group of elements or integers.
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is one member of a family of haemopoietic growth factors (HGFs) which have a similar predicted tertiary configuration (Parry et al, 1988) and whose receptors also belong to a common family (Gearing et al, 1989, Bazan, 1990). This family of haemopoietic growth factors includes, for example, in addition to GM-CSF, the cytokines IL-2, IL-3, IL-5, IL-6 and IL-10. A distinct subfamily comprising GM-CSF, IL-3 and IL-5 can be discerned based on structural similarities (Goodall et al, 1993) and on their ability to interact with a common receptor component (Lopez et al, 1992).
Human GM-CSF (hGM-CSF) comprises 127 amino acids and is available in recombinant form (rhGM-CSF). The hGM-CSF receptor has also been cloned and shown to comprise a binding (.alpha.) chain exhibiting low affinity binding to GM-CSF (Gearing et al, 1989) and a second (.beta.) chain which does not measurably bind GM-CSF by itself but it allows the formation of a high affinity receptor when co-expressed with the .alpha. chain (Hayashide et al, 1990).
GM-CSF exhibits a range of activities extending over neutrophil, eosinophil and monocyte lineages. Specifically, GM-CSF stimulates the progenitors of these cells to proliferate and differentiate to become mature cells. In addition, it stimulates mature cells to greater function. The stimulation of mature cells results in greater capacity to phagocytose and kill micro-organisms, kill antibody-coated tumour cells and parasites and generate superoxide anion (O.sub.2.sup.-) in response to various stimuli. The purpose of this activation is presumed to enable the mature cells to become better effector cells in inflammatory reactions.
Therapeutically, the HGFs form an important group of molecules for their actual or potential properties. For example, the main indications for GM-CSF are for its effects on progenitor cells or mature cells. Using its effects on progenitor cells, GM-CSF is used in the treatment of bone marrow failure as seen in aplastic anaemia or chemotherapy or AIDS-induced marrow suppression. In the treatment of infections, the capacity to stimulate mature cells is especially relevant. The capacity of GM-CSF-activated neutrophils and eosinophils to kill tumour cells that have bound antibody is especially remarkable and could be used in tumour therapy.
However, despite the actual and potential benefits of HGFs, they can exhibit some detrimental side effects. For example, GM-CSF can exhibit toxicity due to stimulation of mature cells causing blood vessel damage or thrombosis. The eosinophilia caused by GM-CSF appears especially damaging in this regard. The molecule can also have detrimental effects by stimulating growth of leukaemia cells and tumour cells of non-haemopoietic origin and stimulating production of inflammatory mediators.
International Patent Application No. PCT/AU89/00177 and an article by Lopez et al. (1992) disclose amino acid variants of GM-CSF which have exhibited reduced potency. These variants were investigated further for their potential as GM-CSF antagonists. However, the variants cause classical stimulation at concentrations 100 fold greater compa

REFERENCES:
Gough et al. (1984) Nature, vol. 309, pp. 763-767.
J.F. Bazan (1990) "Haemopoietic Receptors and Helical Cytokines" Immunology Today 11:350-54.
B.J. Brandhuber et al. (1987) "Three-Dimensional Structure of Interleukin-2" Science 238:1707-1709.
M. A. Contreras et al. (1983) "Iodine Monochloride (IC1) Iodination Techniques" Methods in Enzymology 92:277-292.
M.J. Elliott, et al. (1990) "IL-3 and Granulocyte-Macrophage Colony-Stimulating Factor Stimulate Two Distinct Phases of Adhesion in Human Monocytes" The Journal of Immunology 145(1):167-176.
J.C. Gasson, et al. (1986) "High-Affinity Binding of Granulocyte-Macrophage Colony-Stimulating Factor to Normal and Leukemic Human Myeloid Cells" Proc. Natl. Acad. Sci. USA 83:669-673.
D.P. Gearing, et al. (1989) "Expression Cloning of a Receptor for Human Granulocyte-Macropahge Colony-Stimulating Factor" The EMBO Journal 8(12):3667-3676.
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K. Hayashida, et al. (1990) "Molecular Cloning of a Second Subunit of the Receptor for Human Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF): Reconstitution of a High-Affinity GM-CSF Receptor" Proc. Natl. Acad. Sci. USA 87:9655-9659.
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A.F. Lopez, et al. (1986) "Recombinant Human Granulocyte-Macrophage Colony-Stimulating Factor Stimulates In Vitro Mature Human Neutrophil and Eosinophil Function, Surface Receptor Expression, and Survival" J. Clin. Invest. 78:1220-1228.
A.F. Lopez, et al. (1988) "Recombinant Human Interleukin-3 Stimulation of Hematopoiesis in Humans: Loss of Responsiveness With Differentiation in the Neutrophilic Myeloid Series" Blood 72(5):1797-1804.
A.F. Lopez, et al. (1992) "Residue 21 of Human Granulocyte-Macrophage Colony-Stimulating Factor is Critical for Biological Activity and for High But Not Low Affinity Binding" The EMBO Journal 11(3):909-916.
J.H. Morrissey et al. (1981) "Silver Stain for Proteins in Polyacrylamide Gels: A Modified Procedure with Enhanced Uniform Sensitivity" Analytical Biochemistry 117: 307-310.
D.A.D. Parry, et al. (1988) "Conformational Homologies Among Cytokines: Interleukins and Colony Stimulating Factors" Journal of Molecular Recognition 1(3):107-110.
H. Towbin, et al. (1979) "Electrophoretic Transfer of Proteins from Polyacrylamide Gels to Nitrocellulose Sheets: Procedure and Some Applications" Proc. Natl. Acad. Sci. USA 76:4350-4354.
G.G. Wong et al. (1985) "Human GM-CSF: Molecular Cloning of the Complementary DNA and Purification of the Natural and Recombinant Proteins" Science 228:810-815.
M.J. Zoller et al. (1984) "Oligonucleotide-Directed Mutagenesis: A Simple Method Using Two Oligonucleotide Primers and a Single-Stranded DNA Template" DNA 3(6):479-488.
S.M. Zurawski, et al. (1989) "Mouse Interleukin-2 Structure-Function Studies: Substitutions in the First .alpha.-Helix Can Specifically Inactivate p70 Receptor Binding and Mutations in the Fifth .alpha.-Helix Can Specifically Inactivate p55 Receptor Binding" The EMBO Journal 8(9):2583-2590.

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