Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Structurally-modified antibody – immunoglobulin – or fragment...
Patent
1995-06-02
1998-05-05
Caputa, Anthony C.
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Structurally-modified antibody, immunoglobulin, or fragment...
4241411, 4241431, 435326, 435334, 53038822, A61K 39395, A61K 3940, A61K 3942, C07K 1600
Patent
active
057470324
DESCRIPTION:
BRIEF SUMMARY
This invention relates to monoclonal antibodies specific for the receptor for human granulocyte-macrophage colony stimulating factor (hGM-CSF), and to compositions and methods utilizing these antibodies.
BACKGROUND AND PRIOR ART
Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a growth and differentiation factor for a variety of haemopoietic progenitor cells (including those for neutrophils, macrophages, eosinophils, megakaryocytes and erythroid cells) and can also functionally activate mature neutrophils, eosinophils and macrophages (Metcalf, D., The Molecular Control of Blood Cells, Harvard University Press, Cambridge, Mass. (1988); Gough and Nicola, "Granulocyte-Macrophage Colony-Stimulating, Factor," In Colony-Stimulating Factors: Molecular and Cellular Biology, Dexter et al., eds, Marcel Dekker Inc., NY, pp. 111-153 (1990); Gasson, J. C., Blood:77:1131-1145 (1991); Crosier et al., "Granulocyte-Macrophage Colony-Stimulating Factor," In Human Cytokines: Handbook for Basic and Clinical Research, Aggarwal and Gutterman, eds., Blackwell, Oxford, pp. 238-252 (1992)). All of the actions of GM-CSF are thought to be mediated through the interaction of GM-CSF with specific cell surface receptors. These receptors consist of a specific .alpha.-chain (PCT/AU90/00342, published as WO 91/02063) (Gearing et al., Embo J. 8:3667-3676 (1989)), which binds GM-CSF with low-affinity, and a common .beta.-chain, which by itself does not bind GM-CSF with detectable affinity, and is shared by the .alpha.-chains for the interleukin-3 and interleukin-5 receptors (Kitamura et al., Cell 66:1165-1174 (1991); Tavernier et al., Cell 66:1175-1184 (1991)). The .alpha.-.beta. complex generates high-affinity binding sites for GM-CSF, and is required for cell signalling (Kitamura et al., PNAS (USA) 88:5082-5086 (1991)). However, the mechanism of conversion of the low affinity receptor to high affinity is not yet understood.
Since murine models of excess GM-CSF production (Lang et al., Cell 51:675-686 (1987); Johnson et al., EMBO J. 8:441-448 (1989)) have indicated that a variety of disease states can result from over-production of GM-CSF and consequent macrophage accumulation, and since clinical trials of GM-CSF have indicated that some disease states can be exacerbated by the action of GM-CSF (Grant and Heel, Drug 43:516-560 (1992)), we believe that antibodies that inhibit GM-CSF action may have clinical utility. Moreover, since several human myeloid leukemias have been shown both to possess GM-CSF receptors and to respond to GM-CSF by proliferation (Begley et al., Leukemia 1:1-8 (1987); Griffin et al., Blood 67:1448-1453 (1986); Kelleher et al., Leukemia 2:211-215 (1988); Onetto-Pothier et al., Blood 75:59-66 (1990)); Baldwin et al., Blood 73:1033-1037 (1989)), we believe that such antibodies could be used to suppress leukaemic cell proliferation or to target leukemic cells for antibody-mediated killing. Finally we believe that identification of the antibody epitope on the GM-CSF receptor .alpha.-chain recognized by neutralizing antibody will aid in the design of selective peptide and non-peptide antagonists of GM-CSF action.
We have generated a panel of monoclonal antibodies that specifically recognize the human GM-CSF receptor .alpha.-chain, and one of these inhibits the capacity of GM-CSF to bind to its cellular receptor and to biologically stimulate cells that bear GM-CSF receptors. Surprisingly, this inhibition occurs on cells that bear either the .alpha.-chain of the receptor alone (FD-A5 cells), or which bear the high-affinity .alpha.-.beta. complex (AML 193 cells, human bone marrow cells).
SUMMARY OF THE INVENTION
According to a first aspect, the invention provides monoclonal antibodies specific for hGM-CSF receptor, which antibodies have the ability to inhibit the biological activity of hGM-CSF. Preferably the monoclonal antibodies of the invention are able to bind to both the high affinity and to the low-affinity GM-CSF receptor.
In a preferred embodiment, the monoclonal antibody is KI-2B7-17-A.
According to
REFERENCES:
patent: 5322838 (1994-06-01), Silberstein et al.
Nicola, N. A. et al., "Neutralizing and Nonneutralizing Monoclonal Antibodies to the Human Granulocyte-Macrophage Colony-Stimulating Factor Receptor .alpha.-Chain," Blood 82(6):1724-1731 (1993).
Baldwin et al., "Nonhematopoietic Tumor Cells Express Functional GM-CSF Receptors," Blood 73:1033-37 (Mar. 1989).
Begley et al., "Primary Human Myeloid Leukemia Cells: Comparative Responsiveness to Proliferative Stimulation by GM-CSF or G-CSF and Membrane Expression of CSF Receptors," Leukemia 1:1-8 (Jan. 1987).
Crosier et al., "Granulocyte-Macrophage Colony-Stimulating Factor," Human Cytokines: Handbook for Basic and Clinical Research, Aggarwal and Gutterman, eds., Blackwell, Oxford, pp. 238-252 (1992).
Gasson, J.C., "Molecular Physiology of Granulate-Macrophage Colony-Stimulating Factor," Blood 77(6):1131-45 (Mar. 15, 1991).
Gearing et al., "Expression Cloning of a Receptor for Human Granulocyte-Macrophage Colony-Stimulating Factor," Embo J. 8(12):3667-76 (1989).
Gough and Nicola, "Granulocyte-Macrophage Colony-Stimulating Factor," Colony-Stimulating Factors: Molecular and Cellular Biology, Dexter et al., eds, Marcel Dekker Inc., NY, pp. 111-153 (1990).
Grant & Heel, "Recombinant Granulocyte-Macrophage Colony-Stimulating Factor (rGM-CSF): A Review of its Pharmacological Properties and Prospective Role in the Management of Myelosuppression," Drugs 43(4):516-560 (Apr. 1992).
Griffin et al., "Effects of Recombinant Human GM-CSF on Proliferation of Clonogenic Cells in Acute Myeloblastic Leukemia," Blood 67:1448-53 (May 1986).
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Johnson et al., "A Lethal Myeloproliferative Syndrome in Mice Transplanted with Bone Marrow Cells Infected with a Retrovirus Expressing Granulocyte-Macrophage Colony Stimulating Factor," EMBO J. 8(2):441-448 (1989).
Kelleher et al., "Binding of Iodinated Recombinant Human GM-CSF to the Blast Cells of Acute Myeloblastic Leukemia," Leukemia 2:211-215 (Apr. 1988).
Kitamura et al., "Expression Cloning of the Human IL-3 Receptor cDNA Reveals a Shared .beta. Subunit for the Human IL-3 and GM-CSF Receptors," Cell 66:1165-1175 (Sep. 20, 1991).
Kitamura et al., "Reconstitution of Functional Receptors for Human Granulocyte Macrophage Colony-Stimulating Factor (GM-CSF): Evidence that the Protein Encoded by the AIC2B cDNA is a subunit of the Murine GM-CSF Receptor," PNAS (USA) 88:5082-86 (Jun. 1991).
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Lang et al., "Transgenic Mice Expressing a Hemopoietic Growth Factor Gene (GM-CSF) Develop Accumulations of Macrophages, Blindness, and a Fatal Syndrome of Tissue Damage," Cell 51:675-86 (Nov. 20, 1987).
Metcalf et al., "Low-Affinity Placenta-Derived Receptor for Human Granulocyte-Macrophage Colony-Stimulating Factor Can Deliver a Proliferative Signal to Murine Hemopoietic Cells," PNAS (USA) 87:4670-4674 (Jun. 1990).
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Nicola and Metcalf, "Binding, Internalization and Degradation of .sup.125 I-Multipotential Colony-Stimulating Factor (Interleukin-3) by FDCP-1 Cells," Growth Factors 1:29-39 (1988).
Onetto-Pothier et al., "Characterization of Granulocyte-Macrophage Colony-Stimulating Factor Receptor on the Blast Cells of Acute Myeloblastic Leukemia," Blood 75:59-66 (Jan. 1, 1990).
Tavernier et al., "A Human High Affinity Interleukin-5 Receptor (IL5R) is Composed of an IL-5 Specific .alpha. Chain and a .beta. Chain Shared with the Receptor for GM-CSF," Cell 66:1175-84 (Sep. 20, 1991).
Bolton and Hunter, "The Labelling of Proteins to High Specific Radioactivities by Conjugation to a .sup.125 I-Cont
Boyd Andrew Wallace
Layton Judith Eleanor
Metcalf Donald
Nicola Nicos Antony
Wycherley Kaye
Amrad Corporation Limited
Caputa Anthony C.
Navarro Mark
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