Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Patent
1995-04-18
1998-03-10
Fitzgerald, David L.
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
514 12, 514 13, 514 14, 514 15, 514 16, 514 17, 514 18, 514 19, 530350, 530399, 530381, 435 71, 435 691, A61K 3816, C07K 14745
Patent
active
057261474
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
The present invention relates to a functional mutant of human tissue factor (mhuTF) that binds Factor VII or activated Factor VII (VIIa) but is substantially free of procoagulant cofactor activity. The mutant human tissue factor is useful as a diagnostic and therapeutic reagent.
BACKGROUND
Based on a common folding pattern, proteins may be assigned to fewer than 1000 protein families (Chothia, Nature, 357:543-544 (1992) and Gonnet et al., Science, 256:1443-1445 (1992). Despite the conservation of overall structure, these families of proteins are often characterized by a large repertoire of specificities, as demonstrated, for example, by the immunoglobulin superfamily. Protein-modules are the building blocks which are conserved within a protein family. Among the receptors for various growth and differentiation regulating hormones, structural predictive algorithms identified a common protein motif, now referred to as the cytokine receptor homology domain as described by Bazan, Proc. Natl. Acad. Sci., USA, 87:6934-6938 (1990) and Thoreau et al., FEBS Lett., 282:26-31 (1991). This domain consists of a pair of structurally similar modules which were proposed to adopt a seven .beta.-strand fold with similarity (Bazan, supra and Patthy, Cell, 61:13-14 (1990) to the domain 2 of CD4 Cell, 71:671-678 (1992)!. Experimental support for the proposed structure of the cytokine receptor homology domain was provided by the crystallographic solution of the three dimensional structure of the growth hormone receptor (GHR), a member of this receptor family as described by De Vos et al., Science, 255:306-312 (1992).
Tissue factor (TF) has been predicted to be a distant member of the cytokine receptor family, with structural similarity closer to the Haemostasis, 66:67-79 (1991)! than to the receptors for growth hormone, erythropoietin, colony stimulating factors or several of the interleukins. 30:10363-10370 (1991)! by binding of its ligand, the serine protease Factor VIIa (VIIa) resulting in the formation of a catalytically active enzyme-cofactor complex as described by Edgington et al., supra. In addition, TF serves as a mediator for the auto-activation of VII to VIIa as described by Nakagaki et al., Biochem., 30:10819-10824 (1991).
Upon assembly with TF, VIIa exhibits enhanced catalytic activity evidenced 266:2158-2166, (1991); and Lawson et al., J. Biol. Chem., 267: 4834-4843, 2158-2166, (1991); and Silverberg et al., J. Biol. Chem., 252:8481-8488, (1977); Osterud et al., Proc. Natl. Acad. Sci., USA, 74:5260-5264, (1977); Bom et al., Biochem J., 265: 327-336, (1990); and Lawson et al., J. Biol. Chem., 266:11317-11327, (1991)!. Cleavage of small peptidyl substrates is efficient with micromolar concentrations of the divalent cation, calcium, Ca.sup.2+, whereas, the activation of macromolecular substrates such as the zymogen Factor X (X) require the presence of Ca.sup.2+ at concentrations consistent with saturation of the gamma-carboxylated 266:15719-15725, (1991)!.
By serving as a cell surface receptor for a protease, TF does not follow the functional paradigm of this receptor family which is characterized by binding of growth and differentiation regulating hormones. Nevertheless, ligand binding by TF is mediated entirely by the structurally conserved Ruf et al., J. Biol. Chem., 266:15719-15725 (1991)!, as observed for other cytokine receptors as described by De Vos, supra, and Fukunaga et al., EMBO J., 10:2855-2865 (1991).
The assembly of VIIa with its receptor TF results in the formation of a proteolytically competent enzyme-cofactor complex. In order to define the structure which mediates TF function, a combination of antibody, chemical cross-linking and mutational analysis has been applied. See, Ruf et al., Biochem. J., 278:729-733 (1991); Rehemtulla et al., J. Biol. Chem., 266:10294-10299 (1991); Rehemtulla et al., Biochem. J., 282:737-740 (1992); Ruf et al., Proc. Natl. Acad. Sci., USA, 88:8430-8434 (1991); Ruf et al., J. Biol. Chem., 267:6375-6381 (1992); and Ruf et al., J. Biol. Chem., 267:22206-222
REFERENCES:
patent: 5288629 (1994-02-01), Berkner et al.
Roy et al. 1991. J. Biol. Chem. 32: 22063-22066.
Sigma Catelogue 1991. p. 745.
Ruf, et al., "Antibody Mapping of Tissue Factor Implicates Two Different Exon-Encoded Regions in Function", Biochem. J., 278: 729-733 (1991).
Rehemtulla, et al., "The Integrity of the Cysteine 186-Cysteine 209 Bond of the Second Disulfide Loop of Tissue Factor is Required for Binding of Factor VII", J.B.C., 266: 10294-10299 (1991).
Rehemtulla, et al., "The Third Trp-Lys-Ser (WKS) Tripeptide Motif in Tissue Factor is Associated with a Function Site", Biochem. J., 282: 737-740 (1992).
Ruf, et al., "Two Sites in the Tissue Factor Extracellular Domain Mediate the Recognition of the Ligand Factor VIIa", PNAS, USA, 88: 8430-8434 (1991).
Ruf, et al., "Cofactor Residues Lysine 165 and 166 Are Critical for Protein Substrate Recognition by the Tissue Factor-Factor VIIa Protease Complex", J.B.C., 267: 6375-6381 (1992).
Ruf, et al., "Tissue Factor Residues 157-167 Are Required for Efficient Proteolytic Activation of Factor X and Factor VII", J.B.C., 267: 22206-22210 (1992).
Rehemtulla, et al., "High Level Expression of Recombinant Human Tissue Factor in Chinese Hamster Ovary Cells as a Human Thromboplastin", Thrombosis & Haemostatis, 65: 521-527 (1991).
Ruf, et al., "Phospholipid-Independent and -Dependent Interactions Required for Tissue Factor Receptor and Cofactor Functions", J.B.C., 266: 2158-2166 (1991).
De Vos, et al., "Human Growth Hormone and Extracellular Domain of Its Receptor: Crystal Strucuture of the Complex", Science, 255: 306-312 (1992).
Bass, et al, "A Systematic Mutational Analysis of Hormone-Binding Determinants in the Human Growth Hormone Receptor", PNAS, USA, 88: 4498-4502 (1991).
Edgington Thomas S.
Ruf Wolfram
Fitting Thomas
Fitzgerald David L.
Holmes Emily
Kemmerer Elizabeth C.
The Scripps Research Institute
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