Drug – bio-affecting and body treating compositions – Immunoglobulin – antiserum – antibody – or antibody fragment,... – Monoclonal antibody or fragment thereof
Patent
1991-10-11
1995-08-22
Wax, Robert A.
Drug, bio-affecting and body treating compositions
Immunoglobulin, antiserum, antibody, or antibody fragment,...
Monoclonal antibody or fragment thereof
424 91, 4241451, 4241581, 435 74, 53038824, 530350, 514 12, C07K 1300, C12Q 100
Patent
active
054441536
DESCRIPTION:
BRIEF SUMMARY
TECHNICAL FIELD
This invention relates to genetically engineered variants of a plasminogen activator inhibitor, PAI-2.
DEPOSITION OF MICROORGANISMS
E. coli strain BTA 1445 was deposited with the American Type Culture Collection of 12301 Parklawn Drive, Rockville Md. 20852, U.S.A. in accordance with the provisions of the Budapest Treaty under accession number ATCC 53585 on Feb. 11, 1987.
BACKGROUND ART
Plasminogen activators (PAs) are serine proteases which convert the abundant extracellular zymogen, plasminogen, into plasmin, an active protease which can promote degradation of all components of the extracellular matrix. (Dano et al. Adv. Cancer Res. 44: 139-266, 1985).
Two different types of PAs have been recognised in mammalian tissues: with a molecular weight of about 70,000, composed of one polypeptide chain containing 527 amino acids. Upon limited digestion with plasmin the molecule is converted to a two-chain activator linked by one disulphide bond. This occurs by cleavage of the Arg 275 - Ile 276 peptide bond yielding a heavy chain (M.sub.r 38,000) derived from the N-terminal part of the molecule and a light chain (M.sub.r 32,000) comprising the COOH-terminal region. The catalytic site located in the light chain of t-PA is composed of His 322, Asp 371 and Ser 478. t-PA specifically catalyses the hydrolysis of an Arg 560 - Val 561 bond in plasminogen. Fibrin has been found to strongly stimulate plasminogen activation by t-PA. 50,000 and occurs in a one-polypeptide and a two polypeptide chain form. The one chain form is an inactive proenzyme, while the two-chain form is the active enzyme. u-PA has a substantial plasminogen activator activity in the absence of fibrin and is not stimulated by its presence. t-PA's high affinity for fibrin suggests that it is mostly associated with a fibrinolytic function while u-PA is associated with extracellular proteolytic events such as tissue remodelling and destruction (i.e. organ involution, inflammatory reactions and particularly in the invasive growth and metastatic spread of malignant tumours).
Experimental use of t-PA and single chain u-PA as thrombolytic agents in man has been promising. However, it has become apparent that PAs may have a less pronounced fibrin specificity in man than was anticipated from several animal models, suggesting a need for further improvement either of the agents or of their administrative schemes in clinical thrombolytic therapy. One possibility is the use of specific fast-acting protein inhibitors of PAs to modulate the systemic fibrinolytic effects of PAs.
Recent evidence suggests that urokinase-mediated plasminogen activation may also play a role in the invasive behaviour of malignant cells. With few exceptions malignant cells release PAs in abnormally high amounts. Ossowski and Reich (Cell 35: 611-619, 1983) reported that anti-urokinase antibodies inhibited the metastasis of human epidermoid carcinoma cells seeded onto chick embryo chorioallantoic membranes. Bergman et al (Proc. Natl. Acad. Sci. 83: 996-1000, 1986) have shown that protease nexin I, a fibroblast-secreted inhibitor of urokinase and plasmin, effectively inhibits the cell mediated degradation of extracellular matrix (ECM) by human fibrosarcoma (HT1080) cells. Finally, Sullivan and Quigley (Cell 45: 905-915, 1986) have demonstrated that a monoclonal antibody to PA inhibits the degradation of ECM by Rous sarcoma virus-transformed chick fibroblasts. It follows from these observations and those of others [e.g. Mignatti et al., Cell 47: 487 (1986); Ossowski, Cell 52: 321 (1988); Reich et al, Cancer Res. 48: 3307 (1988)] that specific protease inhibitors of urokinase may play a critical role in altering the levels of active tumour cell PA in tumour tissue and therefore influence tumour growth and invasion in vivo.
There are other indications that a specific inhibitor of urokinase-type plasminogen activator has a role in modern medicine. PAs are involved in a range of inflammatory conditions such as arthritis. Plasmin can degrade cartilage [Lack, CH & Rogers, HJ (19
REFERENCES:
Dano et al. (1985) Advances in Cancer Research 44:139-266, "Plasminogen Activators, Tissue Degradation, and Cancer".
Ossowski et al. (1983) Cell 35:611-619, "Antibodies to Plasminogen Activator Inhibit Human Tumor Metastasis".
Bergman et al. (1986) Proc. Natl. Acad. Sci. USA 83:996-1000, "Inhibition of Tumor-Cell-Mediated Extracellular Matrix Destruction by a Fibroblast Proteinase Inhibitor, Protease Nexin I".
Sullivan et al. (1986) Cell 45:905-915, "Anticatalytic Monoclonal Antibody to Avian Plasminogen Activator: Its Effect on Behavior of RSV-Transformed Chick Fibroblasts".
Mignatti et al. (1986) Cell 47:487-498, "Tumor Invasion Through the Human Amniotic Membrane: Requirement for a Proteinase Cascade".
Ossowski (1988) Cell 52:321-328, "Plasminogen Activator Dependent Pathways in the Dissemination of Human Tumor Cells in the Chick Embryo".
Reich et al. (1988) Cancer Research 48:3307-3312, "Effects of Inhibitors of Plasminogen Activator, Serine Proteinases, and Collagenase IV on the Invasion of Basement Membranes by Metastatic Cells".
Lack et al. (1958) Nature 182:948-949, "Action of Plasmin on Cartilage".
Werb et al. (May 1977) The New England Journal of Medicine 296(18):1017-1023, "Endogenous Activation of Latent Collagenase by Rheumatoid Synovial Cells".
Mochan et al. (1984) The Journal of Rheumatology 11(2):123-128, "Elevations in Synovial Fluid Plasminogen Activator in Patients with Rheumatoid Arthritis".
Kwaan et al. (1969) Experimental and Molecular Pathology 11:82-88, "Tissue Repair in Presence of Locally Applied Inhibitors of Fibrinolysis".
Grondahl-Hansen et al. (1988) The Journal of Investigative Dermatology 90(6):790-795, "Urokinase- and Tissue-Type Plasminogen Activators in Keratinocytes During Wound Reepithelialization In Vivo."
Sprengers et al. (Feb. 1987) Blood 69(2):381-387, "Plasminogen Activator Inhibitors".
Schleuning et al. (1987) Molecular Cellular Biology 7(12):4564-4567, "Plasminogen Activator Inhibitor 2: Regulation of Gene Transcription During Phorbol Ester-Mediated Differentiation of U-937 Human Histiocytic".
Antalis et al. (1988) Proc. Natl. Acad. Sci. USA 85:985-989, "Cloning and Expression of a cDNA Coding for a Human Monocyte-Derived Plasminogen Activator Inhibitor".
Bunn et al. (1989) Abstracts of the 2nd International Workshop on the Molecular and Cellular Biology of Plasminogen Activation Brookhaven National Laboratory, 22, "Expression of Recombinant Human . . . ".
Huber et al. (Nov. 1989) Biochemistry 28(23):8951-8966, "Implications of the Three-Dimensional Structure of .alpha..sub.1 -Antitrypsin for Structure and Function of Serpins".
Stephens et al. (Aug. 1985) Blood 66(2):333-337, "Minactivin Expression in Human Monocyte and Macrophage Populations".
Richardson et al. (1979) Brit. J. Cancer 40:35-43, "Tissue Distribution and Tumor Localization of 99m-Technetium-Labelled Liposomes in Cancer Patients".
Bengent et al. (Oct. 1982) The Lancet 739-742, "Liposomally Entrapped Second Antibody Improves Tumor Imaging with Radiolabelled (first) Antitumor Antibody".
Yanisch-Perron et al. (1985) Gene 33:103-119, "Improved M13 Phage Cloning Vectors and Host Strains; Nucleotide Sequences of the M13mp18 and pUC19 Vectors".
Coleman et al. (1981) Methods in Enzymology 80:408-414, "Coupled Photometric Assay for Plasminogen Activator".
Luckow et al. (Jan. 1988) Biotechnology 6:47-55, "Trends in the Development of Baculovirus Expression Vectors".
Kruithof et al. (Aug. 1986) The Journal of Biological Chemistry 261(24):11207-11213, "Purification and Characterization of a Plasminogen Activator Inhibitor from the Histiocytic Lymphoma Cell Line U-937".
Andreasen et al. (Jun. 1986) The Journal of Biological Chemistry 261(17):7644-7651, "Plasminogen Activator Inhibitor from Human Fibrosarcoma Cells Binds Urokinase-type Plasminogen Activator, But Not Its . . . ".
Molecular Cloning, A Laboratory Manual, Maniatis et al. (eds), 1st ed. (1982) 153-163, "Technique of Agarose Gel Electrophoresis".
Hanahan (1983) The Journal of Molecular Biol
Goss Neil H.
Richardson Michael A.
Biotech Australia Pty Limited
Schmickel David B.
Wax Robert A.
LandOfFree
Variants of PAI-2 does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Variants of PAI-2, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Variants of PAI-2 will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2142627