FLT-4(FMS-like tyrosine kinase), FLT-15, variants thereof used a

Details FLT-4(FMS-like tyrosine kinase), FLT-15, variants thereof used a FLT-4(FMS-like tyrosine kinase), FLT-15, variants thereof used a

1997-05-12

2000-01-04

Spector, Lorraine

Drug, bio-affecting and body treating compositions

Designated organic active ingredient containing

Peptide containing doai

536 235, 435 691, 530350, 935 9, 935 11, C07K 1471

Patent

active

060110031

DESCRIPTION:

BRIEF SUMMARY
FIELD OF THE INVENTION

This invention relates to substances which inhibit growth factors, in particular, vascular endothelial growth factor (VEGF), methods of inhibiting growth factors and of treating tumours and regulating fertility.


BACKGROUND OF THE INVENTION

A considerable number of human growth factors are now known, many of which have been at least partly characterised. Among them is vascular endothelial growth factor (VEGF), which has been identified in several tissues (Gospodarowicz et al., 1989 PNAS 86, 7311-7315; Conn et al., 1990 PNAS 87, 2628-2632; Tischer et al., 1991 J. Biol. Chem. 266, 11947-11954). As its name suggests, this growth factor is a highly specific mitogen for endothelial cells and is greatly involved in angiogenesis. VEGF is a homodimeric glycoprotein of two 23 kDa subunits exhibiting sequence homology with platelet-derived growth factor A and B chains and placenta growth factor.
The homologous tyrosine kinase receptors fms-like tyrosine kinase receptor (FLT) and kinase insert domain-containing receptor (KDR) function as high-affinity VEGF receptors (de Vries et al., 1992 Science 255, 989-991; Terman et al., 1992 Biochem. Biophys. Res. Commun. 187, 1579-1586). Both FLT and KDR are membrane-spanning receptors that each contain seven immunoglobulin-like domains in the extracellular ligand-binding region, an intracellular tyrosine kinase domain and a transmembrane domain. The transmembrane domain serves to anchor the receptor in the cell membrane of the cells in which it is expressed.
A number of membrane-bound receptor molecules have been found to exist in truncated soluble forms, generated either by proteolytic processing or by alternative splicing of mRNA. Recently, Kendall & Thomas (1993 PNAS 90, 10,705-10,709, and WO94/21679) described the discovery of a soluble form of FLT receptor (sFLT) generated by alternative splicing.
Essentially, Kendall & Thomas screened a human umbilical vein endothelial cell (HUVEC) cDNA library with one probe specific for the 3' end of the fit coding region (encoding the intracellular tyrosine kinase domain) and with another probe specific for the 5' fit coding portion (encoding one of the extracellular N terminal domains). Clones which hybridised with the 5' specific probe but not with the 3' specific probe were selected for further study. In this way, a clone was isolated which encoded a soluble FLT polypeptide lacking the transmembrane domain and the intracellular domain. The truncation resulted from "readthrough" to an intronic termination codon. It was suggested by Kendall & Thomas that the soluble receptor could act as an efficient specific antagonist of VEGF in vivo.
The present invention is based on the discovery of further soluble variants of FLT, the existence of which was not predicted by the teaching of Kendall & Thomas.


SUMMARY OF THE INVENTION

In a first aspect the invention provides an altered, soluble form of the FLT polypeptide being capable of binding to VEGF and therebv exerting an inhibitory effect thereon, the polypeptide comprising five or fewer complete immunoglobulin-like domains. Preferably, the altered FLT polypeptide comprises four or fewer complete Ig-like domains. The altered soluble FLT polypeptide inhibits VEGF by preventing it binding to its natural receptors, fit and KDR, present on the surface of target cells. Surprisingly, such truncated forms, lacking a major extracellular portion of the molecule, are believed to retain affinity for VEGF.
The term "soluble" as used herein is intended to refer to altered forms of the FLT polypeptide which do not comprise a transmembrane domain and thus generally do not become associated with the cell membrane of cells in which the molecule is expressed. In particular, the invention provides soluble altered forms of the FLT polypeptide consisting substantially of four or five complete immunoglobulin-like domains.
In a particular embodiment the invention provides an altered, soluble form of FLT having at its C-terminus a region substantially having the amino acid sequence of t

REFERENCES:
patent: 5861484 (1999-01-01), Kendall et al.

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