Antibodies which bind the G-CSF receptor extracelluar domain and

Details Antibodies which bind the G-CSF receptor extracelluar domain and Antibodies which bind the G-CSF receptor extracelluar domain and

1997-01-21

1999-05-11

Loring, Susan A.

Drug, bio-affecting and body treating compositions

Immunoglobulin, antiserum, antibody, or antibody fragment,...

Monoclonal antibody or fragment thereof

53038822, A61K39/395

Patent

active

059025840

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

The present invention relates generally to cytokine interactive molecules, such as antibodies and other immune reactive molecules, agonists and antagonists. The present invention also provides methods for assaying for the presence of cytokines or receptor associated proteins such as kinases and their function.
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.


BACKGROUND OF THE INVENTION

Granulocyte colony-stimulating factor (G-CSF) stimulates the proliferation and differentiation of neutrophil precursors via interaction with a specific cell surface receptor, the G-CSF receptor (G-CSF-R).
Although the G-CSF-R has been cloned (1) and is functionally active in several different cell types (2), little is known about the mechanism of signal transduction. The G-CSF-R is believed to consist of a single chain that is activated through ligand induced homodimerisation (3) as has been shown for the erythropoietin and growth hormone receptors (EPO-R, GH-R) (4). The G-CSF-R does not contain an intrinsic protein kinase domain (1) although tyrosine kinase activity seems to be required for transduction of the G-CSF signal (5). JAK kinases (6,7) are receptor-associated proteins which are rapidly phosphorylated after receptor activation. In particular, Tyk2 is phosphorylated following interferon .alpha.-receptor (IFN.alpha.-R) activation (8) and JAK2 following the binding of EPO (9), GH (10) and interleukin-3 (IL-3) (11) to their respective receptors.
In work leading up to the present invention, the inventors investigated early signal transduction events resulting from the association of G-CSF with its receptor and the role of JAK1 and JAK2.
In accordance with the present invention, antibodies were prepared to the extracellular domain of G-CSF-R. It has now been surprisingly discovered that G-CSF interaction with G-CSF-R is required for tyrosine phosphorylation of JAK kinases. The antibodies of the present invention now provide for a method of inhibiting G-CSF binding to its receptor and, by consequence, phosphorylation by JAK kinases. The present invention contemplates, therefore, a method for treating G-CSF related disease conditions or JAK1 and JAK2 phosphorylation associated disease conditions which result from G-CSF interaction with its receptor.


SUMMARY OF THE INVENTION

One aspect of the present invention is directed to a composition comprising antibodies or parts, fragments or derivatives thereof to G-CSF-R extracellular domain.
Another aspect of the present invention relates to antibodies to the composition defined above.
Yet another aspect of the present invention contemplates a method for inhibiting, reducing or otherwise decreasing tyrosine phosphorylation of JAK1 or JAK2 in a mammal, said method comprising administering to said mammal a binding effective amount of an antibody or a part, fragment or derivative thereof interactive with G-CSF-R extracellular domain.
Still yet another aspect of the present invention contemplates a method for inhibiting, reducing or otherwise decreasing G-CSF interaction with G-CSF-R in a mammal, said method comprising administering to said mammal, a binding effective amount of an antibody or part, fragment or derivative thereof interactive with G-CSF-R extracellular domain.
In still yet another aspect of the present invention, there is provided agonists and antagonists to G-CSF-R.


BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a photographic representation showing tyrosine phosphorylation of JAK kinases in response to G-CSF (AML-193 cells).
AML-193 cells were incubated with rhG-CSF (100 ng/ml) for the times indicated (minutes) and lysed. Tyrosine phosphorylated proteins were immunoprecipitated with antiphosphotyrosine antibody 4G10 (.alpha.PY), Upstate Biotechnology Inc. (U

REFERENCES:
patent: 4683295 (1987-07-01), Carson
Sevier. E. Dale et al, Clin Chem, 27(11): 1797-1806, 1981.
Layton, J. E. et al, J. Biol Chem, 266(35): 23815-23823, Dec. 1991.

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