WO2017190059A1 - Stabilisation de monomères de la proinsuline - Google Patents

Stabilisation de monomères de la proinsuline Download PDF

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WO2017190059A1
WO2017190059A1 PCT/US2017/030214 US2017030214W WO2017190059A1 WO 2017190059 A1 WO2017190059 A1 WO 2017190059A1 US 2017030214 W US2017030214 W US 2017030214W WO 2017190059 A1 WO2017190059 A1 WO 2017190059A1
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proinsulin
insulin
dimerization
diabetes
misfolded
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Peter ARVAN
Ming Liu
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University of Michigan System
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University of Michigan System
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/12—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains three hetero rings
    • C07D491/14—Ortho-condensed systems
    • C07D491/147—Ortho-condensed systems the condensed system containing one ring with oxygen as ring hetero atom and two rings with nitrogen as ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/473—Quinolines; Isoquinolines ortho- or peri-condensed with carbocyclic ring systems, e.g. acridines, phenanthridines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A61K31/4738—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/4745—Quinolines; Isoquinolines ortho- or peri-condensed with heterocyclic ring systems condensed with ring systems having nitrogen as a ring hetero atom, e.g. phenantrolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

Definitions

  • compositions and methods for the stabilization of proinsulin monomers for the treatment of poor insulin production, pancreatic beta cell failure, and diabetes therewith are provided herein.
  • misfolded proinsulin is prevented from propagating its deleterious effects by inhibiting the dimerization of proinsulin in general and misfolded proinsulin specifically.
  • Diabetes mellitus type 2 is a long term metabolic disorder that is characterized by high blood sugar and insulin resistance. Pancreatic ⁇ -cells increase insulin
  • compositions and methods for the stabilization of proinsulin monomers and the treatment of poor insulin production, pancreatic beta cell failure, and diabetes therewith.
  • misfolded proinsulin is prevented from propagating its deleterious effects by protecting the dimerization surface of proinsulin in general and misfolded proinsulin specifically.
  • provided herein are methods of treating diabetes (e.g., type II diabetes, MIDY, etc.) in a subject comprising protecting the proinsulin dimerization surface.
  • protecting the dimerization surface of proinsulin comprises administering a pharmaceutical composition to the subject.
  • the pharmaceutical composition binds to the dimerization surface of proinsulin polypeptides and may inhibit the formation of dimers.
  • the pharmaceutical composition binds to the dimerization surface of misfolded proinsulin polypeptides.
  • the pharmaceutical composition binds to the dimerization surface of properly folded proinsulin polypeptides.
  • the pharmaceutical composition is a small molecule, peptide, peptide mimetic, or antibody or fragment thereof.
  • the pharmaceutical composition is a small molecule that may be chemically related to camptothecin, 7 -methoxycamptothecin, 11 -methoxycamptothecin, 7- CH 3 C1- camptothecin, irinotecan, pinafide, and derivatives thereof.
  • compositions comprising a proinsulin dimerization surface protector (PDSP).
  • the protector is a small molecule, peptide, peptide mimetic, or antibody or fragment thereof.
  • the protector binds to the dimerization surface.
  • the protector is a small molecule selected from camptothecin, 7 -methoxycamptothecin, 11- methoxycamptothecin, 7- CH 3 Cl-camptothecin, irinotecan, pinafide, and derivatives thereof.
  • proinsulin dimerization surface protectors for use in treating diabetes.
  • a proinsulin dimerization surface protector for the manufacture of a medicament for treating diabetes. Additional embodiments within the scope herein are described in the Detailed
  • FIG. 1 Proinsulin B-chain tyrosine-16 plays an important role in proinsuin dimerization.
  • 293T cells co-transfected with the plasmids encoding proinsulin(PI)-WT or hProCpepSFGFP-C(A7)Y or C(A7)Y/Y(B16)D at a DNA ratio of 1 : 1.
  • the cells were labeled with 5 Met/Cys for 30 min, lysed with co- immunoprecipitation buffer, and split in half. One half was immunoprecipitated with anti- insulin, the other half was co-immunoprecipitated with anti-GFP, and the proinsulin co- immunoprecipitated with hProCpepGFP mutants was analyzed in the panel C and quantified from 3 independent experiments in the panel D.
  • 293T cells were co-transfected with the plasmids encoding human PI-WT and mouse PI-WT or mutants as indicated. The secretion of human PI-WT in the presence of mouse WT or mutant proinsulin was measured using human Pi-specific RIA.
  • F. 293T cells were co-transfected with the plasmids encoding untagged PI- WT and Myc-tagged PI-WT or mutants as indicated. At 48 h post-transfection, the cells were labeled with 5 S-Met/Cys for 30 min with 0 or 2 h chase as indicated. The chase media (“M”) were collected and cells ("C”) were lysed. The biosynthesis and secretion of WT and mutant proinsulin were analyzed by NuPage under reducing conditions.
  • Fig. 2 Mutating Tyr(B 16) in proinsulin-C(A7)Y partially restores insulin production from co-expressed proinsulin-WT and alleviates beta cell ER stress.
  • B. MIN6 cells were co-transfected with plasmids encoding human proinsulin-WT with either mouse proinsulin- WT or mutants. At 48 h post-transfection, human insulin content in the transfected cells was measured using human insulin specific RIA.
  • C. ⁇ 6 cells were triple-transfected with plasmids encoding BiP-firefly Luciferase and CMV-renilla luciferase plus proinsulin-WT or mutants. 48 h post-transfection, luciferase activities in transfected cells were measured using dual-luciferase assay.
  • FIG. 3 A PDSP docks with the proinsulin dimerization interface, alleviates trans- dominant negative effect of C(A7)Y, and increases insulin production from Akita islets.
  • A. 293T cells were co-transfected with plasmids encoding human proinsulin-WT and mouse proinsulin-C(A7)Y. At 30 h post-transfection, the cells were incubated individually with one of a series of putative PDSPs for 16 h. Secreted human proinsulin-WT was measured by human proinsulin specific RIA.
  • C. and D. 11-MCPT docks with the insulin dimerization surface predicted by the Protein-Protein Interaction Server. E.
  • the islets isolated from Akita mice were pretreated with 3 ⁇ g/mL 11-MCPT for 24 h.
  • the islets were then pulse-labeled with 5 S-Met/Cys for 12 min with 0 or 2 h chase as indicated.
  • the newly synthesized proinsulin and processed insulin were analyzed in panel E, and quantified in panel F.
  • G. and H The islets isolated irom Akita mice were incubated with 3 ⁇ g/mL 11-MCPT for 24 h.
  • the steady state levels of proinsulin and insulin content in the islets were then analyzed by anti-insulin western blotting in panel G, and quantified in panel H.
  • a PDSP alleviates the development and progression of diabetes in.
  • Akita mice A. 6-8 week old male diabetic Akita mice were randomly separated into two groups based on their body weight and blood glucose. The mice were given 11-MCPT (lmg/kg body weight) or vehicle (5% DMSO in saline) daily by intraperitoneal injection for 28 days. The fasting blood glucose levels were monitored once a week. B. and C. On the 21st day of 11 -MCPT treatment, the mice were fasted overnight followed by orally administrated with dextrose (lg/kg body weight). Blood glucose (Panel B) and serum insulin (Panel C) were measured at 0 and 120 min after oral dextrose. D.
  • Islets were isolated from Akita mice treated with 11-MCPT (lmg/kg body weight) or vehicle for 7 days. The isolated islets were immediately fixed and processed for transmission electron microscope.
  • F-H. Islets were isolated irom Akita mice treated with 11- MCPT (lmg/kg body weight) or vehicle for 28 days. The steady state levels of proinsulin and insulin content in the islets were then analyzed by anti-insulin western-blotting in panel F, and quantified in panel G. The ratio of insulin to proinsulin is shown in panel H. Fig. 5.
  • Proinsulin-Y(B 16)D and Y(B 16)A are well folded and secreted.
  • A. 293T cells were transfected with empty vector (EV) or plasmids encoding proinsulin wild-type (WT) or mutants as indicated. At 48 h post-transfection, newly synthesized proinsulin molecules were labeled with 5 S-Met/Cys for 30 min. The biosynthesis and folding of WT or mutant proinsulin were analyzed using tris-tricine-urea-SDS-PAGE under both non-reducing and reducing conditions.
  • the recovery of native proinsulin in the cells expressing proinsulin- WT was set up as 100%.
  • C. and D. 293T cells were transfected and labeled as in the panel A. After labeling, the cells were chased 0 or 2 h. The chase media ("M”) were collected and cells ("C”) were lysed. The biosynthesis and secretion of mutant proinsulins were analyzed by NuPage under reducing conditions in C, and quantified in D.
  • Proinsulin-C(A7)Y/Y(B16)D were misfolded and retained in the ER.
  • Fig. 7. The PDSP, 11 -MCPT, did not affect insulin level in islets from wild-type mice. A. and B. After overnight recovery, the islets isolated from wild-type mice were incubated with 3 ⁇ g/mL 1 1-MCPT for 24 h. The steady state levels of proinsulin and insulin content in the islets were then analyzed by anti-insulin western blotting in the panel A, and quantified in the panel B.
  • Fig. 8 Misfolded mutant proinsulin affecting bystander WT proinsulin, and a target to improve proinsulin ER export and insulin production.
  • Proinsulin forms dimers in the ER.
  • WT wild-type
  • misfolded mutant proinsulin the mutant abnormally interacts with co-expressed bystander WT proinsulin, forming heterodimers and protein aggregates, through which not only affects normal folding and ER export of WT proinsulin but also induces ER stress and beta cell death.
  • Proinsulin dimerization surface PDS is the initiation site that misfolded mutant proinsulin uses to attack bystander proinsulin, leading to beta cell failure and diabetes.
  • Targeting PDS with PDSPs limits interactions of misfolded proinsulin and bystander proinsulin, decreasing trans- dominant effect of misfolded proinsulin, increasing proinsulin export, alleviating ER stress, increasing insulin production, and therefore retarding progression of beta cell failure and diabetes.
  • Fig. 9 Misfolded Akita mutant proinsulin bearing the B16D substitution, which diminishes proinsulin dimerization, diminishes the dominant-negative effect of the misfolded proinsulin on co-expressed bystander proinsulin-WT.
  • Cells (293T) transfected to express Myc-tagged proinsulin-WT along with either untagged proinsulin-WT or untagged Akita mutant proinsulin or untagged Akita mutant proinsulin bearing the B16D substitution were metabolically labeled with radioactive amino acids for 30 min followed by lysis of the cells at time 0 ("No Chase") or time 3 hr.
  • Fig. 10 The dominant-negative behavior of misfolded Akita mutant proinsulin on wildtype (WT) proinsulin, which leads to diabetes, is ameliorated when the WT proinsulin carries the B16D substitution that diminishes proinsulin dimerization.
  • transfected cells were metabolically labeled with radioactive amino acids for 30 min, followed by lysis of the cells ("C") at time 0 or time 3 hr, as indicated. After 3 hr, secretion of proinsulin to the medium (“M”) was also analyzed. Both cell lysates (“C”) and secretion into the media (“M”) were immunoprecipitated with anti-insulin followed by analysis using 4-12% NuPage gel with phosphorimaging to see the cellular or secreted proinsulin. Note that more proinsulin-WT bearing the B16D substitution can be secreted despite co-expression with misfolded Akita mutant proinsulin.
  • Cells (293T) were co-transfected with Myc-tagged proinsulin-WT and either untagged proinsulin-WT or untagged Akita mutant proinsulin.
  • the transfected cells were treated with candidate compounds ⁇ g/mL, structures shown above, but 7-methoxy camptothecin was not examined in this experiment) for 16 hours. At the end of this time, the media were collected and the cells were lysed.
  • the cell lysates (left panel) and media (right panel) were analyzed by immunoblotting with anti-Myc antibody (the lowest band on the gel is the specific Myc-tagged proinsulin- WT). Note that whereas misfolded Akita mutant proinsulin severely inhibits the secretion of Myc-tagged proinsulin-WT in all samples, the presence of 7-chloromethyl-camptothecin partially reverses the inhibition of secretion of proinsulin-WT.
  • Fig. 13 7- CH 3 CI-CPT increases insulin content in Akita islets.
  • Islets were isolated from Akita mice and were recovered overnight in 11.1 mM glucose RPMI medium containing 10% fetal bovine serum. The islets were then incubated with 3 ⁇ g/mL candidate compound 7- CH3CI-CPT or DMSO (control) for 24 hours. The islet lysates were resolved using 4-12% NuPage under reducing conditions, electrotransferred to nitrocellulose, and immunoblotted with anti-insulin. Each sample was run in duplicate; the samples that had been treated with the 7-chloromethyl-camptothecin recovered more protein in the insulin (B-chain) band.
  • the term "comprise” and linguistic variations thereof denote the presence of recited feature(s), element(s), method step(s), etc. without the exclusion of the presence of additional feature(s), element(s), method step(s), etc.
  • diabetes refers to the set of diseases and conditions known collectively as “diabetes mellitus,” including “type 1 diabetes,” “type 2 diabetes,”
  • diabetes during pregnancy
  • MIDY Meat INS-gene-induced Diabetes of Youth
  • the term is used for disorders in which the pancreas produces and/or secretes insufficient amounts of active/properly-folded insulin, and/or in which the cells of the body fail to respond appropriately to insulin (e.g., "insulin resistance") thus preventing cells from absorbing glucose.
  • insulin resistance e.g., insulin resistance
  • Type 1 diabetes also called “insulin-dependent diabetes mellitus” (“IDDM”) and "juvenile-onset diabetes,” is caused by B-cell destruction and/or the inabiulity of the pancreas to produce active insulin, usually leading to absolute insulin deficiency.
  • IDDM insulin-dependent diabetes mellitus
  • juvenile-onset diabetes is caused by B-cell destruction and/or the inabiulity of the pancreas to produce active insulin, usually leading to absolute insulin deficiency.
  • Type 2 diabetes also known as “non-insulin-dependent diabetes mellitus”
  • NIDDM NIDDM
  • adult-onset diabetes is associated with predominant insulin resistance and thus relative insulin deficiency and/or a predominantly insulin secretory defect with insulin resistance.
  • MIDY MIDY
  • WT bystander wild-type proinsulin
  • the term “subject” broadly refers to any animal, including but not limited to, human and non-human mammals (e.g., primates, rodents, dogs, cats, cows, horses, sheep, etc.).
  • the term “patient” typically refers to a subject that is suffering from and/or being treated for a disease or condition (e.g., diabetes, etc.).
  • antibody refers to a whole antibody molecule or a fragment thereof (e.g., Fab, Fab', F(ab')2, Fv, scFv, Fd, diabodies, and other antibody fragments that retain at least a portion of the variable region of an intact antibody. See, e.g., Hudson et al. (2003) Nat. Med. 9: 129-134; herein incorporated by reference in its entirety); it may be a polyclonal or monoclonal antibody, chimeric, a humanized, etc.
  • an antibody or other entity when an antibody or other entity "specifically recognizes” or “specifically binds” an antigen or epitope, it preferentially recognizes the antigen in a complex mixture of proteins and/or macromolecules, and binds the antigen or epitope with affinity which is substantially higher than to other entities not displaying the antigen or epitope.
  • affinity which is substantially higher means affinity that is high enough to enable detection of an antigen or epitope which is distinguished from entities using a desired assay or measurement apparatus.
  • binding affinity having a binding constant (K a ) of at least 10 7 M “1 (e.g., >10 7 M “1 , >10 8 M “1 , >10 9 M “1 , >10 10 M “1 , >10 n M “1 , >10 12 M “1 , >10 13 M “1 , etc.).
  • K a binding constant
  • an antibody is capable of binding different antigens so long as the different antigens comprise that particular epitope.
  • homologous proteins from different species may comprise the same epitope.
  • epitope refers to any polypeptide determinant capable of specifically binding to an immunoglobulin or a T-cell or B-cell receptor.
  • an epitope is a region of an antigen that is specifically bound by an antibody.
  • an epitope may include chemically active surface groupings of molecules such as amino acids, sugar side chains, phosphoryl, or sulfonyl groups.
  • an epitope may have specific three dimensional structural characteristics (e.g., a
  • epitope is defined as “the same” as another epitope if a particular antibody specifically binds to both epitopes.
  • polypeptides having different primary amino acid sequences may comprise epitopes that are the same.
  • epitopes that are the same may have different primary amino acid sequences. Different antibodies are said to bind to the same epitope if they compete for specific binding to that epitope.
  • wild-type refers to a gene or gene product (e.g., protein) that has the characteristics (e.g., sequence) of that gene or gene product isolated from a naturally occurring source, and is most frequently observed in a population.
  • mutant refers to a gene or gene product that displays modifications in sequence when compared to the wild-type gene or gene product.
  • naturally-occurring mutants are genes or gene products that occur in nature, but have altered sequences when compared to the wild-type gene or gene product; they are not the most commonly occurring sequence.
  • synthetic mutants are genes or gene products that have altered sequences when compared to the wild-type gene or gene product and do not occur in nature. Mutant genes or gene products may be naturally occurring sequences that are present in nature, but not the most common variant of the gene or gene product, or “synthetic,” produced by human or experimental intervention.
  • an effective dose or “effective amount” refers to an amount of an agent, e.g., a PDSP, which results in a desired biological outcome (e.g., protection of the proinsulin dimerization surface).
  • administering refers to the act of providing a therapeutic, prophylactic, or other agent to a subject for the treatment or prevention of one or more diseases or conditions.
  • routes of administration to the human body are through space under the arachnoid membrane of the brain or spinal cord (intrathecal), the eyes (ophthalmic), mouth (oral), skin (topical or transdermal), nose (nasal), lungs (inhalant), oral mucosa (buccal), ear, rectal, vaginal, by injection (e.g., intravenously, subcutaneously, intratumorally, intraperitoneally, etc.) and the like.
  • the term "treat,” and linguistic variations thereof, encompasses therapeutic measures, while the term “prevent” and linguistic variations thereof, encompasses prophylactic measures, unless otherwise indicated.
  • co-administration refers to the administration of at least two agent(s) or therapies to a subject (e.g., a PDSP and one or more therapeutic agents). In some embodiments, the co-administration of two or more agents or therapies is concurrent. In other embodiments, a first agent/therapy is administered prior to a second agent/therapy.
  • a first agent/therapy is administered prior to a second agent/therapy.
  • formulations and/or routes of administration of the various agents or therapies used may vary. The appropriate dosage for co-administration can be readily determined by one skilled in the art. In some
  • agents or therapies when agents or therapies are co-administered, the respective agents or therapies are administered at lower dosages than appropriate for their administration alone.
  • co-administration is especially desirable in embodiments where the co-administration of the agents or therapies lowers the requisite dosage of a potentially harmful (e.g., toxic) agent(s), and/or when co-administration of two or more agents results in sensitization of a subject to beneficial effects of one of the agents via co-administration of the other agent.
  • composition refers to the combination of an active agent (e.g., PDSP) with a carrier, inert or active, making the composition especially suitable for diagnostic or therapeutic use in vitro, in vivo or ex vivo.
  • active agent e.g., PDSP
  • carrier inert or active
  • compositions that do not substantially produce adverse reactions, e.g., toxic, allergic, or immunological reactions, when administered to a subject.
  • the term "pharmaceutically acceptable carrier” refers to any of the standard pharmaceutical carriers including, but not limited to, phosphate buffered saline solution, water, emulsions (e.g., such as an oil/water or water/oil emulsions), and various types of wetting agents, any and all solvents, dispersion media, coatings, sodium lauryl sulfate, isotonic and absorption delaying agents, disintgrants (e.g., potato starch or sodium starch glycolate), and the like.
  • the compositions also can include stabilizers and
  • preservatives examples include carriers, stabilizers and adjuvants, see, e.g., Martin,
  • the term “derivative” refers to a compound that is structurally related to a references compound (e.g., camptothecin), but comprises one or more structural modifications (e.g., substitutions).
  • a derivative maintains the functional activity of the reference compound (e.g., protection of the dimerization surface of proinsulin monomers) or exhibits an enhancement of the functional activity of the reference compound.
  • substituted refers to the modification of a position on a molecule with one or more additional group(s).
  • substituent groups may be selected from, but are not limited to: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxyl, alkoxy, mercaptyl, cyano, halo, carbonyl, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, perhaloalkyl, perfluoroalkyl, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.
  • compositions and methods for protection of the dimerization surface of proinsulin monomers and the treatment of poor insulin production, pancreatic beta cell failure, and diabetes therewith.
  • misfolded proinsulin is prevented from propagating its deleterious effects by protecting the dimerization surface of proinsulin in general and misfolded proinsulin specifically.
  • a proinsulin variant Y(B16)D does not impair intracellular transport of proinsulin-WT, but limits abnormal interactions between WT and mutant proinsulin, permitting the ER export of WT proinsulin, alleviating ER stress, and increasing active insulin production.
  • PDSPs Proinsulin Dimerization Surface Protectors
  • Proinsulin misfolding with endoplasmic reticulum (ER) stress and decreased pancreatic beta cell mass are hallmarks of pancreatic beta cell failure and diabetes (ref. 7; incorporated by reference in its entirety).
  • MIDY affected patients are heterozygotes carrying proinsulin misfolding-inducing mutations in one of their two INS gene alleles (refs. 8-12; incorporated by reference in their entireties).
  • one normal INS allele is ordinarily enough to maintain normoglycemia (ref. 13, 14; incorporated by reference in their entireties)
  • MIDY patients typically develop severe insulin-deficient diabetes (ref. 8-10, 12; incorporated by reference in their entireties).
  • misfolded mutant proinsulin interacts with proinsulin-WT in the ER, impairing the ER export of proinsulin-WT, decreasing bioactive insulin production (refs. 4,5, 15; incorporated by reference in their entireties).
  • preventing these intermolecular proinsulin interactions limits attack of potentially active insulin by misfolded mutant proinsulin, allowing active, bystander proinsulin-WT to exit from the ER.
  • provided herein are methods and compositions for treating diabetes (e.g., type II diabetes, MIDY, etc.) by inhibiting the dimerization of proinsulins, and thereby allowing export of monomeric proinsulin.
  • diabetes e.g., type II diabetes, MIDY, etc.
  • by protecting the dimerization surface of proinsulin monomers the propagation of the effect of misfolded proinsulin onto properly-folded and potentially active proinsulins through dimerization thereto is inhibited.
  • any suitable methods and/or compositions for protecting the dimerization surface of proinsulin are within the scope herein.
  • dimerization of misfolded proinsulin to properly-folded proinsulin is inhibited.
  • an inhibitor binds to a feature on the dimerization surface of misfolded proinsulin, but not properly-folded proinsulin, thereby preventing dimerization of the misfolded proinsulin (e.g., to other misfolded proinsulins as well as to properly-folded proinsulins), while allowing dimerization of properly-folded proinsulins.
  • an inhibitor binds to a feature on the dimerization surface of both misfolded and properly-folded proinsulin, thereby inhibiting the dimerization of all proinsulins (e.g., misfolded, properly-folded, or therebetween).
  • an inhibitor binds to misfolded proinsulin (e.g., at the dimerization surface or elsewhere), but not properly -folded proinsulin, and sequesters the bound proinsulin from dimerization.
  • the inhibitor prevents dimerization through the location of its binding (e.g., to the dimerization surface); by altering the structure of the dimerization surface; by binding to another location on proinsulin that is important for dimerization; and/or by having a bulky structure (e.g., antibody) that, when bound to proinsulin, isn't compatible with dimerization.
  • an agent binds to misfolded, but not properly-folded proinsulin, and promotes the dimerization of two bound/misfolded proinsulins to each other. In some embodiments, an agent binds to misfolded, but not properly-folded proinsulin, and promotes the oligomerization of of multiple bound/misfolded proinsulins to each other. In some embodiments, by promoting the dimerization and/or oligomerization of misfolded proinsulins to each other, dimerization of misfolded proinsulin to properly -folded proinsulin is inhibited.
  • an agent binds to properly-folded, but not misfolded proinsulin, and promotes the dimerization of two bound/properly-folded proinsulins to each other. In some embodiments, by promoting the dimerization of properly-folded proinsulins to each other, dimerization of misfolded proinsulin to properly -folded proinsulin is inhibited.
  • compositions that bind to the dimerization surface of proinsulin and/or inhibit dimerization of proinsulin.
  • such compositions associate with, interact with, and/or bind directly to the dimerization surface of proinsulin.
  • compositions interact with another portion of proinsulin, but cause a structural change that disfavors/inhibits/prevents dimerization.
  • compositions comprise peptides, peptide mimetics, polypeptide, antibodies, antibody fragments, small molecules, nucleic acids, etc.
  • a composition for inhibiting proinsulin dimerization and/or binding to the dimerization surface is a small molecule compound.
  • exemplary PDSP compounds that find use in embodiments herein include:
  • a composition for inhibiting proinsulin dimerization and/or binding to the dimerization surface is a camptothecin derivative (e.g., 7- methoxy camptothecin, 11-methoxy camptothecin, 7- CH 3 Cl-camptothecin, etc.).
  • a camptothecin derivative comprises a camptothecin core structure with one or more additional substituents at one or more of positions 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, and/or 21.
  • Suitable substituents are any organic substituents understood in the field, for example, those described herein.
  • the camptothecin derivative comprises formula (I):
  • substituent groups may be selected from, but are not limited to: alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, hydroxyl, alkoxy, mercaptyl, cyano, halo, carbonyl, thiocarbonyl, isocyanato, thiocyanato, isothiocyanato, nitro, perhaloalkyl, perfluoroalkyl, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof.
  • one or more of positions 1-21 are modified (e.g., from C, O, or N) to C, O, S, or N.
  • embodiments herein demonstrate that protection of the proinsulin dimerization surface, whether by small molecule inhibitor or genetic mutation of the proinsulin dimerization surface, treats diabetes, increases active insulin production/secretion, and decreases loss of beta cells. Therefore, embodiments herein are not limited to these exemplary compounds. Rather, any compound, other agent, method, or mechanism for inhibiting the dimerization of misfolded proinsulin with bystander (or properly folded) proinsulin finds use in the embodiments herein.
  • compounds within the scope herein comprise modified versions, conjugates, and/or derivatives of camptothecin, 7-methoxy camptothecin, 11-methoxy camptothecin, 7- CH 3 C1- camptothecin, irinotecan, and pinafide.
  • compounds not structurally- related to camptothecin, 7-methoxy camptothecin, 11-methoxy camptothecin, 7- CH 3 C1- camptothecin, irinotecan, pinafide, and derivatives thereof find use herein.
  • compositions such as peptides, antibodies, etc. that inhibit proinsulin dimerization are within the scope herein.
  • compositions comprising a PDSP (e.g., 11- MCPT, 7-MCPT, pinafide, etc.), alone or in combination with at least one other agent, such as a stabilizing compound, and may be administered in any sterile, biocompatible pharmaceutical carrier, including, but not limited to, saline, buffered saline, dextrose, and water.
  • a PDSP e.g., 11- MCPT, 7-MCPT, pinafide, etc.
  • dosages for any one patient depends upon many factors, including the patient's size, body surface area, age, the particular compound to be administered, sex, time and route of administration, general health, and interaction with other drugs being concurrently administered.
  • these pharmaceutical compositions may be formulated and administered systemically or locally.
  • Techniques for formulation and administration may be found in the latest edition of "Remington's Pharmaceutical Sciences” (Mack Publishing Co, Easton Pa.). Suitable routes may, for example, include oral or transmucosal administration; as well as parenteral delivery, including intramuscular, subcutaneous, intramedullary, intrathecal, intraventricular, intravenous, intraperitoneal, or intranasal administration.
  • compositions may be formulated in aqueous solutions, preferably in physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiologically buffered saline.
  • physiologically compatible buffers such as Hanks' solution, Ringer's solution, or physiologically buffered saline.
  • penetrants appropriate to the particular barrier to be permeated are used in the formulation. Such penetrants are generally known in the art.
  • the pharmaceutical compositions are formulated using pharmaceutically acceptable carriers well known in the art in dosages suitable for oral administration.
  • Such carriers enable the pharmaceutical compositions to be formulated as tablets, pills, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral or nasal ingestion by a patient to be treated.
  • compositions include compositions wherein the active ingredients (e.g., 11 -MCPT, 7-MCPT, pinafide, etc.) are contained in an effective amount to achieve the intended purpose.
  • an effective amount of a PDSP may be that amount that restores a normal (non-diseased) rate of insulin mediated glucose metabolism. Determination of effective amounts is well within the capability of those skilled in the art, especially in light of the disclosure provided herein.
  • compositions may contain suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
  • suitable pharmaceutically acceptable carriers comprising excipients and auxiliaries that facilitate processing of the active compounds into preparations that can be used pharmaceutically.
  • the preparations formulated for oral administration may be in the form of tablets, dragees, capsules, or solutions.
  • compositions of the present invention may be manufactured in a manner that is itself known (e.g., by means of conventional mixing, dissolving, granulating, dragee- making, levigating, emulsifying, encapsulating, entrapping or lyophilizing processes).
  • compositions for parenteral administration include aqueous solutions of the active compounds in water-soluble form. Additionally, suspensions of the active compounds may be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils such as sesame oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances that increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions.
  • compositions for oral use can be obtained by combining the active compounds with solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores.
  • suitable excipients are carbohydrate or protein fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; starch from corn, wheat, rice, potato, etc; cellulose such as methyl cellulose, hydroxypropylmethyl-cellulose, or sodium carboxymethylcellulose; and gums including arabic and tragacanth; and proteins such as gelatin and collagen.
  • disintegrating or solubilizing agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof such as sodium alginate.
  • Dragee cores are provided with suitable coatings such as concentrated sugar solutions, which may also contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and/or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures.
  • Dyestuffs or pigments may be added to the tablets or dragee coatings for product identification or to characterize the quantity of active compound, (e.g., dosage).
  • compositions for oral administration include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a coating such as glycerol or sorbitol.
  • the push-fit capsules can contain the active ingredients mixed with a filler or binders such as lactose or starches, lubricants such as talc or magnesium stearate, and, optionally, stabilizers.
  • the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycol with or without stabilizers.
  • compositions comprising a PDSP formulated in a pharmaceutical acceptable carrier may be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.
  • Conditions indicated on the label may include treatment of obesity, diabetes, insulin resistance, or weight loss.
  • the pharmaceutical composition may be provided as a salt and can be formed with many acids, including but not limited to hydrochloric, sulfuric, acetic, lactic, tartaric, malic, succinic, etc. Salts tend to be more soluble in aqueous or other protonic solvents that are the corresponding free base forms.
  • the preferred preparation may be a lyophilized powder in 1 mM-50 mM histidine, 0.1%-2% sucrose, 2%-7% mannitol at a pH range of 4.5 to 5.5 that is combined with buffer prior to use.
  • a therapeutically effective dose may be estimated initially from cell culture assays and/or animal models (particularly murine models).
  • a therapeutically effective dose refers to that amount of a PDSP that ameliorates symptoms of the disease state or unwanted condition. Toxicity and therapeutic efficacy of such compounds can be determined by standard pharmaceutical procedures in cell cultures or experimental animals, e.g., for determining the LD 50 (the dose lethal to 50% of the population) and the ED 50 (the dose therapeutically effective in 50% of the population).
  • the dose ratio between toxic and therapeutic effects is the therapeutic index, and it can be expressed as the ratio LD 5 o/ED 5 o. Compounds that exhibit large therapeutic indices are preferred.
  • the dosage of such compounds lies preferably within a range of circulating concentrations that include the ED 50 with little or no toxicity.
  • the dosage varies within this range depending upon the dosage form employed, sensitivity of the patient, and the route of administration. The exact dosage is chosen by the individual clinician in view of the patient to be treated. Dosage and administration are adjusted to provide sufficient levels of the active moiety or to maintain the desired effect. Additional factors which may be taken into account include the severity of the disease state; age, weight, and gender of the patient; diet, time and frequency of administration, drug combination (s), reaction sensitivities, and
  • Typical dosage amounts may vary from 0.1 to 100,000 micrograms, up to a total dose of about 1 g, depending upon the route of administration.
  • Guidance as to particular dosages and methods of delivery is provided in the literature (See, U. S. Pat. Nos. 4,657,760; 5,206,344; 5,225,212; WO2004/097009, or WO2005/075465, each of which are herein incorporated by reference).
  • the therapeutics herein are combined or used in combination with other agents useful in the treatment of diabetes.
  • the therapeutic effectiveness of one of the compounds described herein may be enhanced by administration of an adjuvant (e.g., by itself the adjuvant may only have minimal therapeutic benefit, but in combination with another therapeutic agent, the overall therapeutic benefit to the patient is enhanced).
  • Such other agents, adjuvants, or drugs may be administered, by a route and in an amount commonly used therefor, simultaneously or sequentially with a compound as disclosed herein.
  • a pharmaceutical composition containing such other drugs in addition to the compound disclosed herein may be utilized, but is not required.
  • a therapeutic described in embodiments herein is combined with an anti-obesity and/or an anti-diabetes therapy.
  • a therapeutic described in embodiments herein is provided with a meglitinide, e.g., to stimulate the release of insulin.
  • exemplary meglitinides are repaglinide (Prandin) and nateglinide (Starlix).
  • a therapeutic described in embodiments herein is provided with a sulfonylurea, e.g., to stimulate the release of insulin.
  • Exemplary sulfonylureas are glipizide (Glucotrol), glimepiride (Amaryl), and glyburide (DiaBeta, Glynase).
  • a therapeutic described in embodiments herein is provided with a dipeptidyl peptidase-4 (DPP-4) inhibitor, e.g., to stimulate the release of insulin and/or to inhibit the release of glucose from the liver.
  • DPP-4 (DPP-4) inhibitors are saxagliptin (Onglyza), sitagliptin (Januvia), and linagliptin (Tradjenta).
  • a compound described herein is provided with a biguanide, e.g., to inhibit the release of glucose from the liver and/or to improve sensitivity to insulin.
  • An exemplary biguanide is metformin (Fortamet, Glucophage).
  • a therapeutic described in embodiments herein is provided with a thiazolidinedione, e.g., to improve sensitivity to insulin and/or to inhibit the release of glucose from the liver.
  • exemplary thiazolidinediones include but are not limited to rosiglitazone (Avandia) and pioglitazone (Actos).
  • a compound described herein is provided with an alpha- glucosidase inhibitor, e.g., to slow the breakdown of starches and some sugars.
  • alpha-glucosidase inhibitors include acarbose (Precose) and miglitol (Glyset).
  • a compound as described herein is provided with an injectable medication such as an amylin mimetic or an incretin memetic, e.g., to stimulate the release of insulin.
  • an exemplary amylin mimetic is pramlintide (Symlin); exemplary incretin mimetics include exenatide (Byetta) and liraglutide (Victoza).
  • a compound described herein is provided with insulin.
  • the technology is not limited to any particular form of insulin, but encompasses any form of insulin.
  • the therapeutic described in embodiments herein are used with an insulin injection.
  • more than one additional therapy e.g., drug or other biologically active composition or compound
  • more than one additional therapy e.g., drug or other biologically active composition or compound
  • the therapeutics herein are administered without administering insulin and/or replace the need for insulin therapy in a subject.
  • a PDSP is co-administered with one or more additional therapeutic agents or medical interventions.
  • co-administration involves co-formulation of two or more agents together into the same medicament.
  • the agents are in separate formulations but are administered together, either simultaneously or in sequence (e.g., separated by one or more minutes, hours, days, etc.).
  • the co-administered agent may be provided at a lower dose than would normally be administered if that agent were being used in isolation to treat the disease or condition.
  • kits for use in the instant methods comprise one or more containers comprising a PDSP or a pharmaceutically acceptable salt thereof, and/or a second agent, and in some variations further comprise instructions for use in accordance with any of the methods provided herein.
  • the kit may further comprise a description of selecting an individual suitable treatment.
  • Instructions supplied in the kits of the technology are typically written instructions on a label or package insert (e.g., a paper insert included with the kit), but machine-readable instructions (e.g., instructions carried on a magnetic or optical storage disk) are also contemplated.
  • the kit is a package containing a sealed container comprising any one of the preparations described above, together with instructions for use.
  • the kit can also include a diluent container containing a pharmaceutically acceptable diluent.
  • the kit can further comprise instructions for mixing the preparation and the diluent.
  • the diluent can be any pharmaceutically acceptable diluent.
  • Well known diluents include 5% dextrose solution and physiological saline solution.
  • the container can be an infusion bag, a sealed bottle, a vial, a vial with a septum, an ampoule, an ampoule with a septum, an infusion bag, or a syringe.
  • the containers can optionally include indicia indicating that the containers have been autoclaved or otherwise subjected to sterilization techniques.
  • the kit can include instructions for administering the various solutions contained in the containers to subjects.
  • the technology also relates to methods of treatment with a PDSP.
  • a method for treating a subject in need of such treatment with an effective amount of a PDSP or a salt thereof.
  • some subjects in need of compositions according to the technology have diabetes, insulin resistance, obesity, etc.
  • the method involves administering to the subject an effective amount of a PDSP in any one of the pharmaceutical preparations described above, detailed herein, and/or set forth in the claims.
  • the subject can be any subject in need of such treatment.
  • the technology is in connection with a PDSP or salts thereof.
  • Such salts include, but are not limited to, bromide salts, chloride salts, iodide salts, carbonate salts, and sulfate salts.
  • methods of treatment comprising:
  • the administration causes one or more of: a reduction in or elimination of one or more symptoms of the condition, prevention of increased severity of one or more symptoms of the condition, and/or reduction, prevention, or elimination of further diseases or conditions.
  • the methods provided comprise testing a subject for a disease or condition followed by administering a PDSP, a derivative thereof, or a pharmaceutically acceptable salt thereof, alone or in combination with other agents.
  • methods comprise administering to a subject a PDSP, alone or in combination with other agents, followed by testing the subject for a disease or a condition.
  • methods comprise testing a subject for a disease or condition followed by administering a PDSP, alone or in combination with other agents, followed by a second round of testing for a disease or condition (e.g., to monitor the effect of the treatment).
  • methods comprise testing a subject for a disease or condition followed by administering a PDSP, followed by a second round of testing for a disease or condition and a second administration of a PDSP, with this second administration being modified in dose, duration, frequency, or administration route in a manner dependent upon the results of the prior testing.
  • a subject is tested to assess the presence, the absence, or the level of a disease, e.g., by assaying or measuring a biomarker, a metabolite, a physical symptom, an indication, etc., to determine the risk of or the presence of the disease and thereafter the subject is treated with a PDSP based on the outcome of the test.
  • a patient is tested, treated, and then tested again to monitor the response to therapy.
  • cycles of testing and treatment may occur without limitation to the pattern of testing and treating (e.g., test/treat, test/treat/test, test/treat/test/treat, test/treat/test/treat/test, test/treat/treat/test/treat/treat, etc.), the periodicity, or the duration of the interval between each testing and treatment phase.
  • the technology provided comprises use of a PDSP in the manufacture of a medicament for the treatment of a condition. In some embodiments, the technology provides a PDSP for the treatment of a condition.
  • Proinsulin initiates dimerization in the ER (ref. 6; incorporated by reference in its entirety), yet dimerization is not required for ER export of proinsulin (ref. 16; incorporated by reference in its entirety).
  • the interface between proinsulin or insulin monomers involves only a subset of insulin B-chain residues (ref. 17; incorporated by reference in its entirety).
  • pancreatic beta cells expressing proinsulin-C(A7)Y the cells expressing the proinsulin-C(A7)Y/Y (B16)D double mutant did not lose detectable insulin
  • proinsulin-WT immunofluorescence derived from endogenous proinsulin-WT (Fig. 2A), and did not lose detectable immunoreactive processed human insulin derived from an expressed cDNA encoding human proinsulin-WT (Fig. 2B).
  • proinsulin-WT could undergo successful intracellular transport (and processing to insulin) in the presence of co-expressed misfolded proinsulin-C(A7)Y/Y (B16)D.
  • proinsulin-WT could undergo successful intracellular transport (and processing to insulin) in the presence of co-expressed misfolded proinsulin-C(A7)Y/Y (B16)D.
  • ER export of proinsulin-WT was a significant reduction in ER stress measured by a BiP promoter- luciferase reporter, compared to cells expressing proinsulin-C(A7)Y (Fig. 2C).
  • proinsulin dimerization interface is a druggable target for treating diabetes involving proinsulin misfolding.
  • silico molecular docking of the dimerization interface was performed to screen a set of 139,735 drug-like small molecules with precisely known structures, as putative Proinsulin Dimerization Surface Protectors (PDSPs). The top 40 scoring compounds were then ordered from the National Cancer Institute Open Chemical Repository for cell based functional testing.
  • Molecular docking indicates that Pinafide and 11-methoxycamptocethixcin (11-MCPT, Fig. 3B) fit at the dimerization interface of insulin monomers (See Fig.
  • islets from Akita mice that express one MIDY mutant Ins 2 allele plus one WT Ins 2 and two WT Ins I alleles were isolated. Despite being only one of four alleles, the product of the MIDY mutant allele is sufficient to impair intracellular transport of much of the bystander proinsulin-WT, bringing about insulin-deficient diabetes refs. 5,15; incorporated by reference in their entireties).
  • Treatment of islets with the 11-MCPT did not affect proinsulin or insulin levels in islets of wild-type control mice (Fig. 7).
  • PDSP-treatment of Akita islets, with no significant effect on proinsulin translation markedly increased newly synthesized proinsulin and fully processed mature insulin by 2 h of chase (Fig. 3E, quantified in Fig. 3F).
  • pancreatic islets demonstrate that PDSPs alleviate dominant-negative behavior of misfolded mutant proinsulin to allow proinsulin-WT to be stabilized and exported from the ER, so that it is be processed and stored as mature insulin.
  • 11-MCPT was administered to Akita males beginning at 6-8 weeks of age when the mice started to develop frank diabetes (ref. 20;
  • pancreatic proinsulin levels at steady state were comparable to that of vehicle-treated Akita mice (Fig. 4F)
  • processed mature insulin was significantly increased (Fig. 4G, ratio quantified in 4H).
  • ER stress in pancreatic beta cells has been implicated in the development and progression of type 1, type 2, and some monogenetic diabetes (refs. 21-24; incorporated by reference in their entireties).
  • proinsulin to misfolding is not only an important potential driver of beta cell ER stress (ref. 25-28; incorporated by reference in their entireties) but exacerbates the problem by propagating misfolding onto newly synthesized bystander proinsulin molecules (refs. 4,5,15; incorporated by reference in their entireties).
  • proinsulin dimerization interface is a site initiating abnormal interactions between misfolded proinsulin and bystander proinsulin- WT in the ER (Fig. 8, left panel).
  • Targeting the proinsulin dimerization interface by PDSPs is effective for limiting the ability of misfolded proinsulin to propagate misfolding to bystanders, increasing insulin production (Fig. 8, right panel), and reducing beta cell secretory failure and diabetes.
  • Misfolded Akita proinsulin accelerates the degradation of co-expressed wildtype bystander proinsulin.
  • proinsulin-Y(B16)DA4fo ' ta when the wildtype bystander proinsulin was co-expressed with proinsulin-Y(B16)DA4fo ' ta, the degradation of wildtype bystander proinsulin was decreased (Fig. 10).
  • Proinsulin-Y(B16)DA4 z ' to has less effect on the secretion of co- expressed proinsulin-WT at the steady state.
  • Garin I E. E., Akerman I, Rubio-Cabezas O, Sweden I, Locke JM, Maestro MA, Alshaikh A, Bundak R, del Castillo G, Deeb A, Deiss D, Fernandez JM, Godbole K, Hussain K, O'Connell M, Klupa T, Kolouskova S, Mohsin F, Perlman K, Sumnik Z, Rial JM, Ugarte E, Vasanthi T; Neonatal Diabetes International Group, Johnstone K, Flanagan SE, Martinez R, Castano C, Patch AM, Fernandez-Rebollo E, Raile K, Morgan N, Harries LW, Castano L, Ellard S, Ferrer J, Perez de Nanclares G, Hattersley AT. Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis. Proc Natl Acad Sci U S A. 107, 3105-31 10 (2010).

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Abstract

L'invention concerne des compositions et des procédés pour la protection de la surface de dimérisation de la proinsuline, et le traitement de la mauvaise production d'insuline, du déficit de cellules bêta pancréatiques et du diabète. En particulier, la propagation des effets délétères de la pro-insuline mal pliée est empêchée par l'inhibition de la dimérisation de la proinsuline en général et de la proinsuline mal pliée en particulier.
PCT/US2017/030214 2016-04-28 2017-04-28 Stabilisation de monomères de la proinsuline Ceased WO2017190059A1 (fr)

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Citations (3)

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Publication number Priority date Publication date Assignee Title
US20070162985A1 (en) * 1996-10-25 2007-07-12 Peter Mose Larsen Diabetes-mediating proteins and therapeutic uses thereof
US20100015046A1 (en) * 2002-12-13 2010-01-21 Immunomedics, Inc. Camptothecin-Binding Moiety Conjugates
US7994186B2 (en) * 2005-04-18 2011-08-09 Kabushiki Kaisha Yakult Honsha Pharmaceutical compositions containing camptothecins

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20070162985A1 (en) * 1996-10-25 2007-07-12 Peter Mose Larsen Diabetes-mediating proteins and therapeutic uses thereof
US20100015046A1 (en) * 2002-12-13 2010-01-21 Immunomedics, Inc. Camptothecin-Binding Moiety Conjugates
US7994186B2 (en) * 2005-04-18 2011-08-09 Kabushiki Kaisha Yakult Honsha Pharmaceutical compositions containing camptothecins

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Title
CSORBA ET AL.: "Abnormal proinsulin congeners as autoantigens that initiate the pathogenesis of Type 1 diabetes", MEDICAL HYPOTHESES, vol. 64, no. Issue 1, 2005, pages 186 - 191, XP004729061 *
LIU ET AL.: "Mutant INS- Gene Induced Diabetes of Youth: Proinsulin Cysteine Residues Impose Dominant-Negative Inhibition on Wild-Type Proinsulin Transport", PLOS ONE, vol. 5, no. 10, 2010, pages 1 - 13, XP055436789 *
WINTER ET AL.: "Catalytic Activity and Chaperone Function of Human Protein-disulfide Isomerase Are Required for the Efficient Refolding of Proinsulin", THE JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 277, no. 1, 2002, pages 310 - 317, XP055436786 *

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