WO1991017767A1 - Method of treating inhibition of dipeptidyl aminopeptidase type iv - Google Patents

Method of treating inhibition of dipeptidyl aminopeptidase type iv Download PDF

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Publication number
WO1991017767A1
WO1991017767A1 PCT/US1991/003571 US9103571W WO9117767A1 WO 1991017767 A1 WO1991017767 A1 WO 1991017767A1 US 9103571 W US9103571 W US 9103571W WO 9117767 A1 WO9117767 A1 WO 9117767A1
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WIPO (PCT)
Prior art keywords
tat
protein
binding
inhibition
sample
Prior art date
Application number
PCT/US1991/003571
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French (fr)
Inventor
W. Bachovchin William
Andrew G. Plaut
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New England Medical Center Hospitals, Inc.
Tufts University
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Filing date
Publication date
Application filed by New England Medical Center Hospitals, Inc., Tufts University filed Critical New England Medical Center Hospitals, Inc.
Publication of WO1991017767A1 publication Critical patent/WO1991017767A1/en

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4813—Exopeptidases (3.4.11. to 3.4.19)

Definitions

  • This invention relates to treating diseases associated with inhibition of physiologically significant enzymes.
  • DP-IV Dipeptidyl aminopeptidase
  • EC number 3.4.14.5 serine protease
  • CD-4+ and some CD-8+ T-cells and in low amounts in the central nervous system. It is thought to be involved in T-cell activation and immune regulation.
  • HIV the virus believed to be the causative agent of Acquired Immune Deficiency Syndrome (AIDS)
  • AIDS Acquired Immune Deficiency Syndrome
  • the present invention features a method of treating, in a human patient, a disease state associated with inhibition of DP-IV by a protein by interfering with the inhibition caused by the protein.
  • the disease state involves immunosuppression, e.g., such as that associated with HIV infection.
  • the method involves interfering with the HIV protein Tat, a protein encoded by HIV which inhibits antigen-induced, but not mitogen-induced, lymphocyte proliferation in cell culture systems.
  • Tat causes DP-IV inhibition and thus immunosuppression.
  • the method of the invention preferably involves interfering with that binding, e.g., by competitive inhibition using a substance capable of binding to Tat to inhibit DP-IV-Tat binding; a preferred substance includes DP-IV or a Tat-binding fragment or analog thereof.
  • Tat-DP-IV interaction also permits the exploitation of that interaction in the treatment of a different class of diseases, in which immunosuppression is desired, e.g. , autoimmune diseases such as rheumatoid arthritis and SLE, as well as malignancies such as T-cell leukemias.
  • That method of effecting immunosuppression in a human patient in need of immunosuppression includes administering to the patient an immunosuppressive amount of Tat protein or a DP-IV-binding fragment or analog thereof.
  • the invention also provides an assay for measuring the amount of Tat protein, and thus HIV activity, in a sample, e.g., a blood sample from an AIDS patient being monitored, that includes the steps of adding a pre-determined amount of DP-IV to the sample and measuring the level of DP-IV activity as an inverse measure of the amount of Tat protein in the sample.
  • a sample e.g., a blood sample from an AIDS patient being monitored
  • the level of DP-IV activity is measured colorimetrically.
  • the invention provides an effective treatment for patients suffering from immunosuppressive diseases such as AIDS in which DP-IV activity is inhibited.
  • the course of the therapy can be monitored readily by measuring the amount of Tat protein in a serum sample taken from the patient to which DP-IV has been added; the extent to which DP-IV activity is inhibited is a measure of the amount of Tat protein in the sample.
  • the invention also provides an effective means of inducing immunosuppression in patients suffering from certain diseases by administering Tat protein.
  • Fig. 1 is the nucleotide sequence and deduced amino acid sequence of DP-IV.
  • Fig. 2 is the amino acid sequence of Tat protein. The Tat-DP-IV Interaction
  • Tat protein found in patients infected with AIDS inhibits the activity of DP-IV.
  • T-cells die they are not replenished at a sufficiently high rate, causing the patient to become immuno-compromised.
  • HIV may act to cause T-cell depletion at least in part indirectly, by production of the Tat protein, which binds to and inhibits DP-IV, and prevents DP-IV from fulfilling its normal function in the T-cell proliferation process.
  • DP-IV a Tat-binding fragment or analog thereof
  • Administration is preferably by intravenous injection, so that DP-IV is placed directly into the bloodstream.
  • Other forms of administration e.g., oral, topical, intramuscular, intraperitoneal, parenteral, nasal, or suppository
  • Known techniques may be used to improve the efficacy and decrease the side effects of IV-administered DP-IV.
  • DP-IV can be modified by attachment to the enzyme of numerous polyethylene glycol (PEG) molecules.
  • PEG modification of the enzyme could increase half-life and in addition prevent administered enzyme from triggering an unwanted immune response.
  • PEG treatment has been employed successfully with the enzyme adencsine deaminase (produced by Enzon, Inc., New Jersey).
  • Tat could also be removed by administration of antibody (monoclonal or polyclonal) to Tat. Specificity can be enhanced by producing the antibody using, as an immunogen, a region of Tat which binds specifically to DP-IV.
  • transition state analogs of DP-IV substrates bind tightly to and inhibit DP-IV; these analogs, described in Bachovchin et al. U.S. Serial No. 510,274, filed April 17, 1990, hereby incorporated by reference, contain the DP-IV-binding unit Ala-boro Pro. Antibodies to these transition state analogs can be expected to bind specifically to Tat.
  • the amount of DP-IV administered is selected to cause the total circulating DP-IV level to be higher than the Tat protein level. In this way, a portion of the DP-IV is available to bind to the Tat protein, thereby causing it to be eliminated from the body, and the remaining portion is available to replenish depleted DP-IV levels in the body. Once normal DP-IV levels are restored, the body can begin replenishing depleted T-cells. Once normal immune function has been restored, the immune system may be able to more effectively combat HIV.
  • the proper DP-IV dosage is selected by first measuring the level of Tat protein in the patient. This is preferably done by titration, i.e., by adding a pre-determined amount of DP-IV to a serum sample taken from the patient and then measuring the extent to which the Tat protein inhibits DP-IV activity, using standard protocols. Once the Tat protein level is known, an excess of DP-IV (e.g. , 2-3 times the molar Tat level) is administered to the patient, in a conventional pharmaceutically acceptable carrier, e.g., saline. Typical dosages are 1 - 500 mg/kg/day. AIDS patients may require periodic, e.g., daily, administration of DP-IV for life, much as a diabetic requires regular insulin injections for life.
  • DP-IV can be administered in conjunction with other therapies, e.g., anti-viral agents such as AZT.
  • DP-IV administeration could also be carried in conjunction with administeration of one or more products of DP-IV enzymatic action, e.g., cleaved cytokines, to replenish those products depleted by DP-IV deficiency.
  • Cytokines e.g., IL-1 B and IL-2, which might be acted upon by DP-IV could be administered as well.
  • Both DP-IV and Tat protein have been cloned and expressed, and can be made in quantity using conventional recombinant cell growth techniques.
  • DP-IV is described in Hong et al., Proc. Natl. Acad. Sci.
  • DP-IV nucleotide and amino acid sequence of DP-IV is shown in Fig. 1.
  • the Tat protein is described in Frankel et. al., Proc. Natl. Acad. Sci. USA 86:7397-7401, and the amino acid sequence of Tat protein is shown in Fig. 2.
  • Appropriate DP-IV or Tat-binding fragments or analogs of each protein can be determined using standard screening techniques.
  • a second approach to therapeutically interfering with binding between Tat protein and DP-IV is to prepare a chromatography column containing DP-IV (or a Tat-binding fragment or analog thereof) . Blood from the patient is then passed through the column as in kidney dialysis. The DP-IV in the column binds Tat protein in the blood, thereby removing it from the blood. The cleansed blood is then returned to the patient.
  • Other embodiments are within the following claims.
  • the above-described procedures can be modified to treat patients suffering from diseases characterized by an excess of white blood cells such as leukemia by substituting Tat protein for DP-IV in the therapeutic method.

Abstract

A method of treating, in a human patient, a disease state associated with inhibition of DP-IV by a protein by interfering with the inhibition caused by the protein.

Description

METHOD OF TREATING INHIBITION OF DIPEPTIDYL AMINOPEPTIDASE TYPE IV
Background of the Invention This invention relates to treating diseases associated with inhibition of physiologically significant enzymes.
Dipeptidyl aminopeptidase ("DP-IV") is a serine protease (EC number 3.4.14.5) present in many microbes, mammalian cells, and tissues, e.g., renal tubule cells, intestinal epithelium, and blood plasma. It is also present on the surfaces of human CD-4+ and some CD-8+ T-cells, and in low amounts in the central nervous system. It is thought to be involved in T-cell activation and immune regulation. Patients infected with HIV, the virus believed to be the causative agent of Acquired Immune Deficiency Syndrome (AIDS), exhibit significantly lowered DP-IV activities. Summary of the Invention
The present invention features a method of treating, in a human patient, a disease state associated with inhibition of DP-IV by a protein by interfering with the inhibition caused by the protein. In- preferred embodiments, the disease state involves immunosuppression, e.g., such as that associated with HIV infection. Preferably, the method involves interfering with the HIV protein Tat, a protein encoded by HIV which inhibits antigen-induced, but not mitogen-induced, lymphocyte proliferation in cell culture systems. We have discovered that, in AIDS patients, Tat causes DP-IV inhibition and thus immunosuppression. Where the deleterious DP-IV inhibition by the Tat protein involves binding of DP-IV to Tat, the method of the invention preferably involves interfering with that binding, e.g., by competitive inhibition using a substance capable of binding to Tat to inhibit DP-IV-Tat binding; a preferred substance includes DP-IV or a Tat-binding fragment or analog thereof.
Our discovery of the DP-IV inhibiting effect of Tat, and the consequent deleterious suppression of the immune system, also makes possible a method of improving immune function in a human patient, by administering to the patient an immune function improving amount of DP-IV. In a patient infected with HIV, such administration can serve the dual therapeutic functions of "soaking up" harmful circulating Tat protein, while at the same time replenishing depleted, immuno- stimulating DP-IV.
Our discovery of the Tat-DP-IV interaction also permits the exploitation of that interaction in the treatment of a different class of diseases, in which immunosuppression is desired, e.g. , autoimmune diseases such as rheumatoid arthritis and SLE, as well as malignancies such as T-cell leukemias. That method of effecting immunosuppression in a human patient in need of immunosuppression includes administering to the patient an immunosuppressive amount of Tat protein or a DP-IV-binding fragment or analog thereof.
The invention also provides an assay for measuring the amount of Tat protein, and thus HIV activity, in a sample, e.g., a blood sample from an AIDS patient being monitored, that includes the steps of adding a pre-determined amount of DP-IV to the sample and measuring the level of DP-IV activity as an inverse measure of the amount of Tat protein in the sample. Preferably, the level of DP-IV activity is measured colorimetrically. The invention provides an effective treatment for patients suffering from immunosuppressive diseases such as AIDS in which DP-IV activity is inhibited. The course of the therapy can be monitored readily by measuring the amount of Tat protein in a serum sample taken from the patient to which DP-IV has been added; the extent to which DP-IV activity is inhibited is a measure of the amount of Tat protein in the sample. The invention also provides an effective means of inducing immunosuppression in patients suffering from certain diseases by administering Tat protein.
Other features and advantages of the invention will be apparent from the following description of the preferred embodiments thereof, and from the claims. Description of the Preferred Embodiments
We first briefly describe the drawings. Drawings
Fig. 1 is the nucleotide sequence and deduced amino acid sequence of DP-IV. Fig. 2 is the amino acid sequence of Tat protein. The Tat-DP-IV Interaction
We have discovered .at Tat protein found in patients infected with AIDS inhibits the activity of DP-IV. As a result, when T-cells die they are not replenished at a sufficiently high rate, causing the patient to become immuno-compromised. We thus believe that HIV may act to cause T-cell depletion at least in part indirectly, by production of the Tat protein, which binds to and inhibits DP-IV, and prevents DP-IV from fulfilling its normal function in the T-cell proliferation process. Therapy
Based on our discovery, we have devised a method for treating patients suffering from immunosuppressive diseases such as AIDS that involves interfering with the ability of Tat protein to bind to DP-IV. One way of accomplishing this is to administer DP-IV (or a Tat-binding fragment or analog thereof) to the patient. Administration is preferably by intravenous injection, so that DP-IV is placed directly into the bloodstream. Other forms of administration (e.g., oral, topical, intramuscular, intraperitoneal, parenteral, nasal, or suppository) may also be used. Known techniques may be used to improve the efficacy and decrease the side effects of IV-administered DP-IV. To prevent rapid removal of the enzyme from the blood by the liver, DP-IV can be modified by attachment to the enzyme of numerous polyethylene glycol (PEG) molecules. PEG modification of the enzyme could increase half-life and in addition prevent administered enzyme from triggering an unwanted immune response. PEG treatment has been employed successfully with the enzyme adencsine deaminase (produced by Enzon, Inc., New Jersey). Tat could also be removed by administration of antibody (monoclonal or polyclonal) to Tat. Specificity can be enhanced by producing the antibody using, as an immunogen, a region of Tat which binds specifically to DP-IV. It has been shown that transition state analogs of DP-IV substrates bind tightly to and inhibit DP-IV; these analogs, described in Bachovchin et al. U.S. Serial No. 510,274, filed April 17, 1990, hereby incorporated by reference, contain the DP-IV-binding unit Ala-boro Pro. Antibodies to these transition state analogs can be expected to bind specifically to Tat.
The amount of DP-IV administered is selected to cause the total circulating DP-IV level to be higher than the Tat protein level. In this way, a portion of the DP-IV is available to bind to the Tat protein, thereby causing it to be eliminated from the body, and the remaining portion is available to replenish depleted DP-IV levels in the body. Once normal DP-IV levels are restored, the body can begin replenishing depleted T-cells. Once normal immune function has been restored, the immune system may be able to more effectively combat HIV.
The proper DP-IV dosage is selected by first measuring the level of Tat protein in the patient. This is preferably done by titration, i.e., by adding a pre-determined amount of DP-IV to a serum sample taken from the patient and then measuring the extent to which the Tat protein inhibits DP-IV activity, using standard protocols. Once the Tat protein level is known, an excess of DP-IV (e.g. , 2-3 times the molar Tat level) is administered to the patient, in a conventional pharmaceutically acceptable carrier, e.g., saline. Typical dosages are 1 - 500 mg/kg/day. AIDS patients may require periodic, e.g., daily, administration of DP-IV for life, much as a diabetic requires regular insulin injections for life. DP-IV can be administered in conjunction with other therapies, e.g., anti-viral agents such as AZT. DP-IV administeration could also be carried in conjunction with administeration of one or more products of DP-IV enzymatic action, e.g., cleaved cytokines, to replenish those products depleted by DP-IV deficiency. Cytokines, e.g., IL-1B and IL-2, which might be acted upon by DP-IV could be administered as well. Both DP-IV and Tat protein have been cloned and expressed, and can be made in quantity using conventional recombinant cell growth techniques. DP-IV is described in Hong et al., Proc. Natl. Acad. Sci. USA 84:7962-66 (1987), and the nucleotide and amino acid sequence of DP-IV is shown in Fig. 1. The Tat protein is described in Frankel et. al., Proc. Natl. Acad. Sci. USA 86:7397-7401, and the amino acid sequence of Tat protein is shown in Fig. 2. Appropriate DP-IV or Tat-binding fragments or analogs of each protein can be determined using standard screening techniques.
A second approach to therapeutically interfering with binding between Tat protein and DP-IV is to prepare a chromatography column containing DP-IV (or a Tat-binding fragment or analog thereof) . Blood from the patient is then passed through the column as in kidney dialysis. The DP-IV in the column binds Tat protein in the blood, thereby removing it from the blood. The cleansed blood is then returned to the patient. Other embodiments are within the following claims. For example, the above-described procedures can be modified to treat patients suffering from diseases characterized by an excess of white blood cells such as leukemia by substituting Tat protein for DP-IV in the therapeutic method.

Claims

CLAIMS 1. A method of treating, in a human patient, a disease state associated with inhibition of DP-IV by a protein, said method comprising interfering with said DP-IV inhibition by said protein.
2. The method of claim l wherein said disease state involves immunosuppression.
3. The method of claim 2 wherein said immunosuppression is associated with HIV infection.
4. The method of claim 3 wherein said protein is HIV Tat protein.
5. The method of claim 4 wherein said DP-IV inhibition by said Tat protein involves DP-IV-Tat binding, and said interfering with inhibition is carried out by interfering with said binding.
6. The method of claim 5 wherein said interfering with said binding is carried out by competitive inhibition using a substance capable of binding to Tat to inhibit DP-IV-Tat binding.
7. The method of claim 6 wherein said substance comprises DP-IV or a Tat-binding fragment or analog thereof.
8. A method of improving immune function in a human patient comprising administering to said patient an immune function improving amount of DP-IV.
9. A method of effecting immunosuppression in a human patient in need of immunosuppression, said method comprising administering to said patient an immunosuppressive amount of Tat protein or a DP-IV-binding fragment or analog thereof.
10. An assay for meausuring the amount of Tat protein in a sample comprising the steps of adding a pre-determined amount of DP-IV to said sample; and measuring the level of DP-IV activity as an indication of the amount of Tat protein in said sample.
11. The assay of claim 10 wherein said level of DP-IV activity is measured colorimetrically.
12. A method of removing Tat protein from a sample of human blood, comprising contacting said sample with a substance which is capable of specifically binding Tat and which is coupled to a solid support.
13. The method of claim 12 wherein said subtance is DP-IV, coupled to a column.
PCT/US1991/003571 1990-05-21 1991-05-21 Method of treating inhibition of dipeptidyl aminopeptidase type iv WO1991017767A1 (en)

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Cited By (27)

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Publication number Priority date Publication date Assignee Title
WO1998050066A1 (en) * 1997-05-07 1998-11-12 Trustees Of Tufts College Potentiation of the immune response through delivery of compounds binding a cytoplasmic dipeptidase
US5965532A (en) * 1996-06-28 1999-10-12 Trustees Of Tufts College Multivalent compounds for crosslinking receptors and uses thereof
EP1084705A2 (en) * 1996-04-25 2001-03-21 Probiodrug Gesellschaft für Arzneimittelforschung mbH Method for lowering blood glucose levels in mammals
US6300314B1 (en) 1998-05-04 2001-10-09 Point Therapeutics, Inc. Hematopoietic stimulation
US6355614B1 (en) 1998-06-05 2002-03-12 Point Therapeutics Cyclic boroproline compounds
US6503882B2 (en) 1997-05-07 2003-01-07 Trustees Of Tufts College Treatment of HIV
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US6703238B2 (en) 1997-09-29 2004-03-09 Point Therapeutics, Inc. Methods for expanding antigen-specific T cells
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US6844316B2 (en) 2001-09-06 2005-01-18 Probiodrug Ag Inhibitors of dipeptidyl peptidase I
US6890905B2 (en) 2001-04-02 2005-05-10 Prosidion Limited Methods for improving islet signaling in diabetes mellitus and for its prevention
US6890904B1 (en) 1999-05-25 2005-05-10 Point Therapeutics, Inc. Anti-tumor agents
US6946480B2 (en) 2002-02-28 2005-09-20 Hans-Ulrich Demuth Glutaminyl based DPIV inhibitors
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US7084120B2 (en) 1998-06-24 2006-08-01 Probiodrug Ag Prodrugs of DP IV-inhibitors
US7109347B2 (en) 2001-06-27 2006-09-19 Probiodrug Ag Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents
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US7368421B2 (en) 2001-06-27 2008-05-06 Probiodrug Ag Use of dipeptidyl peptidase IV inhibitors in the treatment of multiple sclerosis
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US7608577B2 (en) 2001-10-12 2009-10-27 Osi Pharmaceuticals, Inc. Peptidyl ketones as inhibitors of DPIV
US20130089564A1 (en) * 2001-06-06 2013-04-11 Diamedica Inc. Therapeutic Uses of Glandular Kallikrein
US9364521B2 (en) 2012-06-04 2016-06-14 Diamedica Inc. Human tissue kallikrein 1 glycosylation isoforms
US9616015B2 (en) 2012-05-25 2017-04-11 Diamedica Inc. Formulations of human tissue kallikrein-1 for parenteral delivery and related methods
US11857608B2 (en) 2017-03-09 2024-01-02 Diamedica Inc. Dosage forms of tissue kallikrein 1

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US7230074B2 (en) 1991-10-22 2007-06-12 Trustees Of Tufts College Inhibitors of dipeptidyl-aminopeptidase type IV
US6825169B1 (en) 1991-10-22 2004-11-30 Trustees Of Tufts College Inhibitors of dipeptidyl-aminopeptidase type IV
EP1084705A3 (en) * 1996-04-25 2002-05-15 Probiodrug Gesellschaft für Arzneimittelforschung mbH Method for lowering blood glucose levels in mammals
EP1084705A2 (en) * 1996-04-25 2001-03-21 Probiodrug Gesellschaft für Arzneimittelforschung mbH Method for lowering blood glucose levels in mammals
EP2289513A3 (en) * 1996-04-25 2013-07-10 Royalty Pharma Collection Trust Method for decreasing the blood glucose level in mammals
US5965532A (en) * 1996-06-28 1999-10-12 Trustees Of Tufts College Multivalent compounds for crosslinking receptors and uses thereof
US6875737B1 (en) 1996-06-28 2005-04-05 Trustees Of Tufts College Multivalent compounds for crosslinking receptors and uses thereof
US6692753B2 (en) 1997-05-07 2004-02-17 Trustees Of Tufts College Potentiation of the immune response
US6503882B2 (en) 1997-05-07 2003-01-07 Trustees Of Tufts College Treatment of HIV
WO1998050066A1 (en) * 1997-05-07 1998-11-12 Trustees Of Tufts College Potentiation of the immune response through delivery of compounds binding a cytoplasmic dipeptidase
US6040145A (en) * 1997-05-07 2000-03-21 Tufts University Potentiation of the immune response
AU724257B2 (en) * 1997-05-07 2000-09-14 Trustees Of Tufts College Potentiation of the immune response through delivery of compounds binding a cytoplasmic dipeptidase
US6703238B2 (en) 1997-09-29 2004-03-09 Point Therapeutics, Inc. Methods for expanding antigen-specific T cells
US6300314B1 (en) 1998-05-04 2001-10-09 Point Therapeutics, Inc. Hematopoietic stimulation
US6770628B2 (en) 1998-05-04 2004-08-03 Point Therapeutics, Inc. Hematopoietic stimulation
US7067489B2 (en) 1998-05-04 2006-06-27 Point Therapeutics, Inc. Hematopoietic stimulation
US6548481B1 (en) 1998-05-28 2003-04-15 Probiodrug Ag Effectors of dipeptidyl peptidase IV
US6355614B1 (en) 1998-06-05 2002-03-12 Point Therapeutics Cyclic boroproline compounds
US7053055B2 (en) 1998-06-24 2006-05-30 Prosidion Ltd. Compounds of unstable DP IV-inhibitors
US7166579B2 (en) 1998-06-24 2007-01-23 Prosidion Limited Prodrugs of DP IV-inhibitors
US7084120B2 (en) 1998-06-24 2006-08-01 Probiodrug Ag Prodrugs of DP IV-inhibitors
US6949514B2 (en) 1999-05-25 2005-09-27 Point Therapeutics, Inc. Anti-tumor agents
US6890904B1 (en) 1999-05-25 2005-05-10 Point Therapeutics, Inc. Anti-tumor agents
US6949515B2 (en) 1999-08-24 2005-09-27 Probiodrug Ag Effectors of dipeptidyl peptidase IV for topical use
US7335645B2 (en) 1999-08-24 2008-02-26 Probiodrug Ag Effectors of dipeptidyl peptidase IV for topical use
US7435420B2 (en) 2000-10-27 2008-10-14 Probiodrug Ag Dipeptidyl peptidase IV inhibitors for the treatment of anxiety
US7132104B1 (en) 2000-10-27 2006-11-07 Probiodrug Ag Modulation of central nervous system (CNS) dipeptidyl peptidase IV (DPIV) -like activity for the treatment of neurological and neuropsychological disorders
US6890905B2 (en) 2001-04-02 2005-05-10 Prosidion Limited Methods for improving islet signaling in diabetes mellitus and for its prevention
US20130089564A1 (en) * 2001-06-06 2013-04-11 Diamedica Inc. Therapeutic Uses of Glandular Kallikrein
US7368421B2 (en) 2001-06-27 2008-05-06 Probiodrug Ag Use of dipeptidyl peptidase IV inhibitors in the treatment of multiple sclerosis
US7368576B2 (en) 2001-06-27 2008-05-06 Probiodrug Ag Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents
US7109347B2 (en) 2001-06-27 2006-09-19 Probiodrug Ag Dipeptidyl peptidase IV inhibitors and their uses as anti-cancer agents
US7144856B2 (en) 2001-09-06 2006-12-05 Probiodrug Ag Inhibitors of dipeptidyl peptidase I
US6844316B2 (en) 2001-09-06 2005-01-18 Probiodrug Ag Inhibitors of dipeptidyl peptidase I
US7608577B2 (en) 2001-10-12 2009-10-27 Osi Pharmaceuticals, Inc. Peptidyl ketones as inhibitors of DPIV
US6946480B2 (en) 2002-02-28 2005-09-20 Hans-Ulrich Demuth Glutaminyl based DPIV inhibitors
US7371871B2 (en) 2003-05-05 2008-05-13 Probiodrug Ag Inhibitors of glutaminyl cyclase
US7381537B2 (en) 2003-05-05 2008-06-03 Probiodrug Ag Use of inhibitors of glutaminyl cyclases for treatment and prevention of disease
US7462599B2 (en) 2003-10-15 2008-12-09 Probiodrug Ag Use of effectors of glutaminyl and glutamate cyclases
US9616015B2 (en) 2012-05-25 2017-04-11 Diamedica Inc. Formulations of human tissue kallikrein-1 for parenteral delivery and related methods
US9364521B2 (en) 2012-06-04 2016-06-14 Diamedica Inc. Human tissue kallikrein 1 glycosylation isoforms
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