EP3416977A1 - Traitement de lésion cérébrale traumatique ou d'accident vasculaire cérébral - Google Patents

Traitement de lésion cérébrale traumatique ou d'accident vasculaire cérébral

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Publication number
EP3416977A1
EP3416977A1 EP17753766.9A EP17753766A EP3416977A1 EP 3416977 A1 EP3416977 A1 EP 3416977A1 EP 17753766 A EP17753766 A EP 17753766A EP 3416977 A1 EP3416977 A1 EP 3416977A1
Authority
EP
European Patent Office
Prior art keywords
pacap
dose
day
traumatic brain
brain injury
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP17753766.9A
Other languages
German (de)
English (en)
Other versions
EP3416977A4 (fr
Inventor
Torsten FALK
Robin Polt
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
University of Arizona
Arizona's Public Universities
Original Assignee
University of Arizona
Arizona's Public Universities
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Priority claimed from US15/044,924 external-priority patent/US10117907B2/en
Application filed by University of Arizona, Arizona's Public Universities filed Critical University of Arizona
Publication of EP3416977A1 publication Critical patent/EP3416977A1/fr
Publication of EP3416977A4 publication Critical patent/EP3416977A4/fr
Pending legal-status Critical Current

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/57563—Vasoactive intestinal peptide [VIP]; Related peptides
    • 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
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A61K38/2278—Vasoactive intestinal peptide [VIP]; Related peptides (e.g. Exendin)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P39/00—General protective or antinoxious agents

Definitions

  • the present invention relates to a method for treating traumatic brain injury or stroke.
  • the present invention relates to using a glycopeptide PACAP/VIP analogues with enhanced CNS penetration for treatment of traumatic brain injury or stroke.
  • endogenous opioid peptides lumped together under the generic term endorphins, have been the subject of intense study since their discovery in the mid 1970's. Some neuropeptides have the potential for selective pharmacological intervention with fewer off-target side effects. If these naturally occurring opioid peptides and their derivatives could be rendered permeable to the blood-brain barrier (BBB), then a new vista of BBBB
  • the BBB is composed of endothelial cells in the cerebrovascular capillary beds.
  • the BBB acts as a lipophilic barrier to chemical substances, but admits vital nutrients through selective transport proteins for proper function of the CNS.
  • the flow is bidirectional, allowing for export of materials from the CNS and the import of materials from the blood.
  • the BBB represents not only a physical obstacle, but a metabolic one as well, possessing both oxidative enzymes and peptidases such as aminopeptidase, arylamidase, and enkephalinase.
  • metabolically unstable substances e.g. peptides
  • Glycosylation has proven to be a successful methodology to improve both the stability and bioavailability of short peptide "messages" by incorporation of the peptide pharmacophore into a glycopeptide.
  • Some BBB penetration studies with opioid glycopeptide agonists based on enkephalins have shown up to 3-fold increases in the rate of brain delivery of these compounds compared with the unglycosylated parent peptides.
  • Recent studies with glycopeptides in artificial membrane systems indicate that amphipathicity of the
  • glycopeptides is an important factor in BBB penetration.
  • type of glycosylation can alter tissue distribution patterns, BBB penetration and peptide/receptor interactions.
  • the endogenous neuropeptide ⁇ -endorphin is a 31 residue naturally occurring opioid peptide agonist that binds to ⁇ and ⁇ opioid receptors. Its N-terminal 5 residues are identical to the Met-Enkephalin sequence, and may be considered to be the pharmacophore or "opioid message.” It was shown that the C-terminal region of ⁇ -endorphin has an
  • B- endorphin consists of the Met-enkephalin peptide sequence at the N-terminus, a hydrophilic linker region from residues 6 through 12, and an amphiphilic helical region between the helix breaker residues Pro(13) and Gly(30).
  • Dynorphin A (1-17) is also an endogenous opioid peptide, but it binds preferentially to the ⁇ opioid receptor and has an N-terminal message segment identical to Leu-Enkephalin. It has been suggested that an address sequence in the C-terminal region imparts selectivity for ⁇ receptors.
  • Dynorphin A displayed an extended and/or random coil structure when subjected to structural analysis by various spectroscopic measurements.
  • a 2D (1) H- MR study in DPC micelle shows that Dynorphin A(l-17) contains a less ordered N- terminal segment, a well-defined a-helix segment spanning between Phe(4) and Pro(10) or Lys(l 1), and a B-turn from Trp(14) to Gln(17).
  • both the a-helix and the C-terminal B-turn are due to dynorphin-micelle interactions, and may be important structural features of the full-length peptide when bound to the cell membrane in vivo.
  • NC potent nociceptin
  • Nociceptin is the endogenous ligand for the recently identified opioid receptor-like 1 receptor (ORL-1).
  • One aspect of the present invention provides glycopeptides that are capable of penetrating the blood-brain-barriers (BBB) for treating traumatic brain injury or stroke.
  • BBB blood-brain-barriers
  • the present inventors have discovered that a variation of glycosylated pleiotropic peptides, pituitary adenylate cyclase-activating polypeptide (PACAP) or vasoactive intestinal peptide (VIP), which can both activate PAC 1; Vn & VIP 2 receptors, can cause
  • PACAP pituitary adenylate cyclase-activating polypeptide
  • VIP vasoactive intestinal peptide
  • these peptides can antagonize these receptors, having anti-inflammatory effects in several models of acute neuronal damage and neurodegenerative diseases, including ALS, PD, AD, HD, migraines, traumatic brain injury, stroke and certain forms of dementia.
  • the present invention provides a method of relieving symptoms of ALS, PD,
  • Such method generally comprises administering to a subject in need thereof an effective amount of a glycosylated PACAP or VIP analogue.
  • One particular aspect of the invention provides a method for treating traumatic brain injury or stroke in a subject.
  • the method comprises administering a therapeutically effective amount of a glycosolated pleiotropic peptide pituitary adenylate cyclase-activating polypeptide (PACAP) or a derivative thereof.
  • PACAP glycosolated pleiotropic peptide pituitary adenylate cyclase-activating polypeptide
  • said PACAP comprises PACAP-27.
  • said PACAP comprises PACAP-38.
  • the therapeutically effective amount can be a unit dose amount of between 0.1 and 10 milligrams per kilo. Such a dose can be administered once a day or twice a day.
  • said traumatic brain injury comprise central nervous system injury. Still in other embodiments, said traumatic brain injury comprises neurotrauma. In some embodiments, said traumatic brain injury is caused by violence, transportation accidents, construction accidents, sports, war, or any other damage to the brain resulting from external mechanical force due to rapid acceleration or deceleration, impact, blast waves, or penetration by a projectile.
  • said glycosylated PACAP or a derivative thereof comprises SEQ ID NO:4, 7, 8, 10 or 11 or a mixture thereof. Yet in other embodiments, said glycosylated PACAP or a derivative thereof comprises a mono- or disaccharide. In some instances, said mono- or disaccharide is O-linked to said glycosylated PACAP or a derivative thereof. In other embodiments, said glycosylated PACAP or a derivative thereof comprises a serine on the C-terminus, and wherein said glycosylate is attached to a hydroxyl group of said serine.
  • Fig. 1 shows increased stability of the Serine glucoside in mouse serum compared to native peptide PACAPi -27 and the corresponding lactoside;
  • Fig. 2 shows PACi - CHO calcium flux of PACAPi -27 and various truncated derivatives, demonstrating that PACAP I-27 SG is potent and efficacious at the PACi receptor.
  • Figs. 3A-3D show PC 12 cell morphology after vehicle versus various PACAP analog treatments.
  • administering when used in conjunction with a therapeutic means to administer a therapeutic directly into or onto a target tissue or to administer a therapeutic to a patient whereby the therapeutic positively impacts the tissue to which it is targeted.
  • administering a composition may be accomplished by oral or rectal administration, injection, infusion, inhalation, absorption or by any method in combination with other known techniques. Such combination techniques include heating, radiation and ultrasound.
  • improves is used to convey that the present disclosure changes the appearance, form, characteristics and/or physical attributes of the tissue to which it is being provided, applied or administered. "Improves” may also refer to the overall physical state of an individual to whom an active agent has been administered. For example, the overall physical state of an individual may "improve” if one or more symptoms of a
  • neurodegenerative disorder are alleviated by administration of an active agent, and is not limited to increased stability or BBB penetration.
  • terapéutica means an agent utilized to treat, combat, ameliorate or prevent an unwanted condition or disease of a patient.
  • terapéuticaally effective amount or “therapeutic dose” as used herein are interchangeable and may refer to the amount of an active agent or pharmaceutical compound or composition that elicits a biological or medicinal response in a tissue, system, animal, individual, or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.
  • a biological or medicinal response may include, for example, one or more of the following: (1) preventing a disease, condition or disorder in an individual that may be predisposed to the disease, condition or disorder but does not yet experience or display pathology or symptoms of the disease, condition or disorder, (2) inhibiting a disease, condition or disorder in an individual that is experiencing or displaying the pathology or symptoms of the disease, condition or disorder or arresting further development of the pathology and/or symptoms of the disease, condition or disorder, and (3) ameliorating a disease, condition or disorder in an individual that is experiencing or exhibiting the pathology or symptoms of the disease, condition or disorder or reversing the pathology and/or symptoms experienced or exhibited by the individual.
  • treating may be taken to mean prophylaxis of a specific disorder, disease or condition, alleviation of the symptoms associated with a specific disorder, disease or condition and/or prevention of the symptoms associated with a specific disorder, disease or condition.
  • the term refers to slowing the progression of the disorder, disease or condition or alleviating the symptoms associated with the specific disorder, disease or condition.
  • the term refers to slowing the progression of the disorder, disease or condition.
  • the term refers to alleviating the symptoms associated with the specific disorder, disease or condition.
  • the term refers to restoring function, which was impaired or lost due to a specific disorder, disease or condition.
  • patient generally refers to any living organism to which the compounds described herein, are administered and may include, but is not limited to, any non-human mammal, primate or human. Such “patients” may or may not be exhibiting the signs, symptoms or pathology of the particular diseased state.
  • a “salt” is any acid addition salt, preferably a pharmaceutically acceptable acid addition salt, including but not limited to, halogenic acid salts such as hydrobromic, hydrochloric, hydrofluoric and hydroiodic acid salt; an inorganic acid salt such as, for example, nitric, perchloric, sulfuric and phosphoric acid salt; an organic acid salt such as, for example, sulfonic acid salts (methanesulfonic, trifluoromethan sulfonic, ethanesulfonic, benzenesulfonic or /?-toluenesulfonic), acetic, malic, fumaric, succinic, citric, benzoic, gluconic, lactic, mandelic, mucic, palmoic, pantothenic, oxalic and maleic acid salts; and an amino acid salt such as aspartic or glutamic acid salt.
  • halogenic acid salts such as hydrobromic, hydrochloric, hydro
  • the acid addition salt may be a mono- or di-acid addition salt, such as a di-hydrohalogenic, di-sulfuric, di-phosphoric or di- organic acid salt.
  • the acid addition salt is used as an achiral reagent which is not selected on the basis of any expected or known preference for interaction with or
  • “Pharmaceutically acceptable salt” is meant to indicate those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of a patient without undue toxicity, irritation, allergic response and the like, and are
  • the term "daily dose amount” refers to the amount of pharmaceutically active compound per day that is administered or prescribed to a patient. This amount can be administered in multiple unit doses or in a single unit dose, in a single time during the day or at multiple times during the day. [0028]
  • a "dose amount” as used herein, is generally equal to the dosage of the active ingredient, which may be administered per day. For example, an effective dose amount may be between about 0.1 and 10 milligrams per kilo, administered 1-2 times a day.
  • unit dose may be taken to indicate a discrete amount of the therapeutic composition that contains a predetermined amount of the active compound.
  • the amount of the active compound is generally equal to the dosage of the active ingredient, which may be administered one or more times per day.
  • the unit dose may be a fraction of the desired daily dose which may be given in fractional increments, such as, for example, one-half or one-third the dosage.
  • the present invention is based in part on the recent discovery that penetration of the blood-brain barrier (BBB) by peptides as well as their stability in vivo is significantly enhanced by glycosylation.
  • BBB blood-brain barrier
  • glycosylation and “glycosylated” means that an amino acid residue is functionalized with a glycosyl group.
  • a glycosyl group is composed of saccharide units. These terms are well-known in the field of peptide and protein chemistry and have such meanings as used herein. In some embodiments, the glycosyl group has at most 8 saccharide units. In other embodiments, the glycosyl group has at most 4 saccharide units.
  • the glycosyl group is at most a disaccharide, i.e., the glycosyl group has at most 2 saccharide units.
  • the total number of saccharide units can range from 1 to 8, inclusive of all specific values and ranges between.
  • glycosyl groups include B-D-glucose, B-maltose, B-lactose, B-melibiose and B-maltotriose.
  • Other examples include sucrose, trehalose, saccharose, maltose, cellobiose, gentibiose, isomaltose and primeveose.
  • glycosyl groups include galactose, xylose, mannose, manosaminic acid, fucose, GalNAc, GlcNAc, idose, iduronic acid, glucuronic acid and sialic acid.
  • glycosylated pleiotropic peptide pituitary adenylate cyclase-activating polypeptide PACAP
  • VIP vascular intestinal peptide
  • TBI traumatic brain injuries
  • Traumatic brain injuries can be categorized as either central nervous system injuries or neurotrauma. Methods of the invention are suitable for treating both of these types of traumatic brain injuries.
  • the TBI is central nervous system injuries.
  • the method of the invention is used to treat neurotrauma.
  • PACAP (SEQ ID NO: 1) is a neuropeptide.
  • Two forms of PACAP have been identified: PACAP-38 and PACAP-27 consisting of 38 amino acids (SEQ ID NO:2) and 27 amino acids (SEQ ID NO:3), which is shortened at the C-terminus.
  • SEQ ID NO: 1 and SEQ ID NO: 2 differs only in that the -OH group on the C-terminus of SEQ ID NO:2 is replaced with -NH 2 group.
  • PACAPi.27 has a 68% homology to VIP. PACAP was first isolated from ovine hypothalamus, and is known to regulate the development, maintenance, function, and plasticity of the nervous system, providing neuroprotective and neurotrophic support.
  • PACAP has been shown to activate 3 closely-related G protein coupled receptors: PACi (which has higher affinity for PACAP), VPACi, and VPAC 2 . These receptors bind to both PACAP and VIP and are expressed on neurons, microglia, and also by many other cell types. Constitutive expression of PACAP and its receptor PACi is believed to confer
  • PACAP neuroprotection to central visceromotor neurons via the PACi receptor.
  • PACAP also promotes cytodestructive functions of microglia (Ml amoeboid ⁇ M2 hypertrophic phenotype), thought to drive ALS disease progression via the VPACi receptor.
  • the ideal drugs for neuroprotection would be PACi agonists at motor neurons to promote neuroprotection in case of ALS, or dopaminergic neurons in case of PD, or hippocampal neurons in case of AD, and in each case VPACi antagonists at microglia to reduce inflammation by maintaining the Ml ('alternatively activated'/resolving anti-inflammatory cells) phenotype vs. the M2 (the classical, proinflammatory macrophages) microglia phenotype or Tau-opathies.
  • glycopeptide analogs of PACAP were prepared with different binding properties to either be only a PACi agonist or only a VPACi antagonist.
  • the glycopeptides of the present invention were produced using Fmoc-based solid-phase peptide methods, and purified by HPLC. Typically, the glycosyl group was linked to the amino acid sequence by an O-linkage to a side chain in the address segment of the sequence. See, for example,
  • FI-MS n Flow-injection tandem mass spectrometry
  • Samples were diluted to a concentration of ⁇ 5 ⁇ of each PACAP analogue, and were incubated at 37 °C for times varying from 1 to 60 minutes. After samples had been incubated for the prescribed amount of time they were prepared for mass spectrometry analysis by withdrawing 10 microliters of solution and spiking with 1 microliter of a 10 ⁇ solution of peptide internal standard (angiotensin II) in 50% acetic acid and subjecting them to a standard CI 8 zip tip desalting. These solutions, once eluted from the zip tip were diluted to 100 ⁇ _, in 50:50 acetonitrile/water with 0.1% formic acid.
  • angiotensin II peptide internal standard
  • Tandem mass spectrometry analysis (MS 3 ) was conducted to yield specific, quantitative signals proportional to the amount of PACAP analogue at each time point. This technique was also used with microdialysate samples from a mouse after i.p. administration of PACAPi_ 27-S G.
  • a custom DNA clone of the human PACi gene with 3 hemagglutinin (HA) tags inserted 3' to the signal peptide sequence was obtained from Genecopoeia (Rockville, MD). The construct was electroporated into Chinese Hamster Ovary (CHO) cells, and selected for with 500 ⁇ g/mL of G418. The resulting population was screened for high expressing clones, and one such clone selected for further analysis.
  • the clonal cell line (PACi-CHO) displayed high receptor expression by immunocytochemistry and Western blot, and showed selective activation of signaling in response to PACAPi_ 27 . This cell line was used for all molecular pharmacology experiments. The cells were maintained in DMEM/F12 with 10%) heat-inactivated FBS, IX penicillin/streptomycin, and 500 ⁇ g/mL G418, at 37°C and 5% C0 2 .
  • Tetra from Molecular Devices (Sunnyvale, CA) set to image calcium flux using the manufacturer's recommended settings and protocols.
  • the day before an experiment the PACi-CHO cells were split into 384 well black walled, clear bottom microplates, 10,000 cells per well. The cells were recovered overnight in growth medium (as above). The next day, the growth medium was replaced with Calcium 6 dye (Molecular Devices) using the manufacturer recommended buffer with 2.5 mM probenecid. The cells were incubated for 2 hours in the culture incubator, and removed during the last 15 minutes to allow equilibration to room temperature. Compound was added to the cells using a 384 tip block, with real time monitoring before, during, and 15 minutes after compound addition. The resulting calcium flux was recorded, and the maximum-minimum response over the entire observation time calculated and reported as the mean ⁇ SEM (4 wells per point, Figure 2).
  • PAC 1R Activation of PAC 1R, VP AC 1R and VPAC2R result in a wide variety of effects throughout the body, both peripherally and centrally.
  • the neuroprotective effects are associated with each of these receptors, but especially with the PAC1R activation.
  • PAC1 receptors are found extensively in the CNS; peripherally they are highly expressed in the adrenal medulla.
  • the rat pheochromocytoma (PC 12) cell line was used as a model for PAC1R activation based on treated cells undergoing differentiation resulting in increased cell-body volume, extension of neurite-like cell processes, along with an antiproliferative action to decrease cell numbers.
  • This cell type also responds in a similar manner to nerve growth factor (NGF) through the tyrosine receptor kinase A (TrkA) receptor, the pathways for the two receptors being complementary, working through different transduction pathways to act synergistically to promote neurite-like process outgrowth.
  • NGF nerve growth factor
  • TrkA tyrosine receptor kinase A
  • PC12 cells were used for assessing the ability of the analogs to initiate a morphological change.
  • the PC12 cells were cultured in RPMI containing 5% heat inactivated fetal bovine serum and 10% horse serum in the presence of 100 units/mL penicillin and 100 microgram/mL streptomycin.
  • the cells were plated on poly-D-Lysine coated 6-well tissue culture plates at a density of 150,000 cells per well in 2 mL media. After 48 hours at 37 °C in 5% C0 2 atmosphere, media exchange was performed and plates were dosed, using the peptide diluent (water) for the control samples.
  • PACAPi_ 27 , PACAP I _ 27- S-G, and PAC AP I _ 27- S- L were used to screen for PACi receptor activation.
  • Four groups of cells were used; one control group (diluent treated) and three treatment groups, each treatment group was exposed to 100 nM concentrations of PACAPi_ 27 , PACAP I _ 27- S-G, or PACAP I _ 27- S- L All groups were run in triplicate.
  • Cells were treated daily for 5 days, then viewed at 400X magnification (Nikon Eclipse TE2000-U).
  • Cell images of each treatment group were captured and compared to the control cells to screen for differentiation and cell body volume increases. Cells having neurite-like process outgrowth were noted and photographed. The neurite-like outgrowth was deemed positive if its length was at least two times the width of the cell body.
  • PACAP derivatives and glycosides were synthesized using solid- phase methods. Some of the representative PACAP derivatives and glycoside analogs of the invention are shown in Table 1.
  • One analog of PACAPi_ 2 7 was produced by replacing the terminal Leucine 27 amide with a Serine lactoside amide (Ser-O- -D-Glc- -D-Gal)
  • ⁇ -Glc cleavage gave 1560.9 m/z, matching the calculated mass for PACAPi -27 with a C-terminal amide. Loss of the glucoside along with peptide backbone cleavage resulted in yi 9 2+ and y 24 2+ ions at 1124.9 and m/z 1391.6.
  • PACAP27-S-G PACAP27-S-G
  • PACAP I _ 2 7-S-G PACAP I _ 2 7-S-G
  • activated PACi with high potency (0.95 ⁇ 0.4 nM and 5.68 ⁇ 2.3 nM respectively, Figure 2 and Table 2).
  • PC12 cells are non-adherent cells, and in spite of using the poly-D-Lysine coated plates, the majority of the cells remained suspended. During the media exchange many of the cells were removed with the spent media. The remaining cells could be visually evaluated for qualitative morphological changes at the end of the treatment period, but meaningful cell quantification could not be done reliably using this approach. It was found that glucoside and lactoside PACAPi -27 derivative treatment produced neurite outgrowth and arborization when compared to vehicle treated cells. See Figures 3 A-D. Qualitatively, it appeared that the arborization caused by PACAPi -27 may be more extensive than that caused by the glucoside and lactoside derivatives, but this could not be quantified.
  • FIGS. 3A-3D show PC12 cell morphology after Vehicle vs PACAP treatment (100 nM).
  • Fig. 3A diluent only.
  • Fig. 3B PACAPi_ 27
  • Fig. 3C PACAP I _ 27 -S-G
  • Fig. 3D PACAP I _ 27- S- L -
  • the cell body volumes all showed increase when treated with each of the PACAP derivatives in Table 1. In all cases the process outgrowths on the treated cells were greater than 2X the cell body width.
  • Endogenous PACAP peptides occur as C-terminal peptide amides that have either 27 or 38 amino acid residues, and are typically regarded as PACi agonists in assays using intact tissue or in cell culture.
  • Use of solid-phase peptide synthesis has allowed replacement of the terminal Leucine amide with glycosides of Serine amide bearing the simple sugars glucose or lactose.
  • These O-linked glycopeptides not only retained their agonist activity on PC12 cell cultures and in the quantitative CHO cell assay, but also showed extended lifetimes in mouse serum, and provided evidence via microdialysis studies that the glycopeptides can cross the blood brain barrier in mice.
  • an effective amount of the PACAP-VIP glycopeptides of the present invention can be administered to a patient in need of treatment in a therapeutically effective unit dose delivery amount of between about 0.1 and 10 milligrams per kilo, typically 1 - 2 doses per day, or even less frequently.
  • the PACAP- VIP glycopeptides can be delivered in a pharmaceutically acceptable carrier.
  • compositions include, but are not limited to, saccharides such as, for example, lactose or sucrose, mannitol or sorbitol, cellulose preparations, calcium phosphates such as tricalcium phosphate or calcium hydrogen phosphate, as well as binders, such as, starch paste, which includes maize starch, wheat starch, rice starch, potato starch, gelatin, tragacanth, methyl cellulose,
  • hydroxypropylmethylcellulose sodium carboxymethylcellulose, polyvinyl pyrrolidone or combinations thereof.
  • compositions may include the active compound described and embodied above, a pharmaceutically acceptable carrier or excipient and any number of additional or auxiliary components known in the pharmaceutical arts such as, for example, binders, fillers, disintegrating agents, sweeteners, wetting agents, colorants, sustained release agents, and the like, and in certain embodiments, the pharmaceutical composition may include one or more secondary active agents.
  • Disintegrating agents such as starches as described above, carboxymethyl-starch, cross-linked polyvinyl pyrrolidone, agar, alginic acid or a salt thereof, such as sodium alginate and combinations thereof.
  • Auxiliary agents may include, for example, flow-regulating agents and lubricants, such as silica, talc, stearic acid or salts thereof, such as magnesium stearate or calcium stearate, polyethylene glycol and combinations thereof.
  • dragee cores may be prepared with suitable coatings that are resistant to gastric juices, such as concentrated saccharide solutions, which may contain, for example, gum arabic, talc, polyvinyl pyrrolidone, polyethylene glycol, titanium dioxide, lacquer solutions and suitable organic solvents or solvent mixtures and combinations thereof.
  • cellulose preparations such as acetylcellulose phthalate or hydroxypropylmethyl- cellulose phthalate may also be used.
  • dye stuffs or pigments may be added to the tablets or dragee coatings, for example, for identification or in order to characterize combinations of active compound doses.
  • compositions of the disclosure can be administered to any animal, and in particular, any mammal, that may experience a beneficial effect as a result of being administered a compound of the disclosure including, but not limited to, humans, canines, felines, livestock, horses, cattle, sheep, and the like.
  • the dosage or amount of at least one compound according to the disclosure provided pharmaceutical compositions of embodiments may vary and may depend, for example, on the use of the pharmaceutical composition, the mode of administration or delivery of the pharmaceutical composition, the disease indication being treated, the age, health, weight, etc. of the recipient, concurrent treatment, if any, frequency of treatment, and the nature of the effect desired and so on.
  • compositions that include one or more compounds of the disclosure in an amount sufficient to treat or prevent diseases such as, for example, cancer.
  • An effective amount of the one or more compounds may vary and may be, for example, from about 0.1 to 10 milligrams per kilo, typically 1-2 doses per day.
  • compositions of the disclosure can be administered by any means that achieve their intended purpose.
  • routes of administration for example, routes of administration
  • encompassed by the disclosure include, but are not limited to, subcutaneous, intravenous, intramuscular, intraperitoneal, buccal, or ocular routes, rectally, parenterally,
  • Embodiments of the disclosure also include methods for preparing pharmaceutical compositions as described above by, for example, conventional mixing, granulating, dragee-making, dissolving, lyophilizing processes and the like.
  • pharmaceutical compositions for oral use can be obtained by combining the one or more active compounds with one or more solid excipients and, optionally, grinding the mixture.
  • Suitable auxiliaries may then be added and the mixture may be processed to form granules which may be used to form tablets or dragee cores.
  • Other pharmaceutical solid preparations include push- fit capsules containing granules of one or more compound of the disclosure that can, in some embodiments, be mixed, for example, with fillers, binders, lubricants, stearate, stabilizers or combinations thereof.
  • Push-fit capsules are well known and may be made of gelatin alone or gelatin in combination with one or more plasticizer such as glycerol or sorbitol to form a soft capsule.
  • compounds of the disclosure may be dissolved or suspended in one or more suitable liquids, such as, fatty oils or liquid paraffin and, in some cases, one or more stabilizers.
  • Liquid dosage formulations suitable for oral administration are also provided.
  • Such embodiments may include one or more compounds of the disclosure in pharmaceutically acceptable emulsions, solutions, suspensions, syrups, and elixirs that may contain, for example, one or more inert diluents commonly used in the art such as, but not limited to, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1,3 -butylene glycol, dimethyl formamide, oils (for example, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, fatty acid derivatives of glycerol (for example, labrasol), tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof.
  • Suspens for example, one or more iner
  • metahydroxide bentonite
  • agar-agar agar-agar
  • tragacanth agar-agar
  • Formulations for parenteral administration may include one or more compounds of the disclosure in water-soluble form, for example, water-soluble salts, alkaline solutions, and cyclodextrin inclusion complexes in a physiologically acceptable diluent which may be administered by injection.
  • Physiologically acceptable diluent of such embodiments may include, for example, sterile liquids such as water, saline, aqueous dextrose, other pharmaceutically acceptable sugar solutions; alcohols such as ethanol, isopropanol or hexadecyl alcohol; glycols such as propylene glycol or polyethylene glycol; glycerol ketals such as 2,2-dimethyl-l,3-dioxolane-4-methanol; ethers such as poly(ethyleneglycol)400; pharmaceutically acceptable oils such as fatty acid, fatty acid ester or glyceride, or an acetylated fatty acid glyceride.
  • sterile liquids such as water, saline, aqueous dextrose, other pharmaceutically acceptable sugar solutions
  • alcohols such as ethanol, isopropanol or hexadecyl alcohol
  • glycols such as propylene glycol or polyethylene glycol
  • formulations suitable for parenteral administration may additionally include one or more pharmaceutically acceptable surfactants, such as a soap or detergent; suspending agent such as pectin, carbomers, methylcellulose, hydroxypropylmethylcellulose, or carboxymethylcellulose; an emulsifying agent;
  • Additional pharmaceutically acceptable oils which may be useful in such formulations include those of petroleum, animal, vegetable or synthetic origin including, but not limited to, peanut oil, soybean oil, sesame oil, cottonseed oil, olive oil, sunflower oil, petrolatum, and mineral oil; fatty acids such as oleic acid, stearic acid, and isostearic acid; and fatty acid esters such as ethyl oleate and isopropyl myristate.
  • Additional suitable detergents include, for example, fatty acid alkali metal, ammonium, and triethanolamine salts; cationic detergents such as dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates; and anionic detergents, such as alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates, and sulfosuccinates.
  • cationic detergents such as dimethyl dialkyl ammonium halides, alkyl pyridinium halides, and alkylamine acetates
  • anionic detergents such as alkyl, aryl, and olefin sulfonates, alkyl, olefin, ether and monoglyceride sulfates, and sulfosuccinates.
  • non-ionic detergents including, but not limited to, fatty amine oxides, fatty acid alkanolamides and polyoxyethylenepolypropylene copolymers or amphoteric detergents such as alkyl-P-aminopropionates and 2- alkylimidazoline quaternary salts, and mixtures thereof may be useful in parenteral formulations of the disclosure.
  • compositions for parenteral administration may contain from about 0.5 to about 25% by weight of one or more of the compounds of the disclosure and from about 0.05% to about 5% suspending agent in an isotonic medium.
  • the injectable solution should be sterile and should be fluid to the extent that it can be easily loaded into a syringe.
  • injectable pharmaceutical compositions may be stable under the conditions of manufacture and storage and may be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • Topical administration includes administration to the skin or mucosa, including surfaces of the lung and eye.
  • Compositions for topical administration may be prepared as a dry powder which may be pressurized or non-pressurized.
  • the active ingredients in admixture are prepared as a finely divided powder.
  • at least 95% by weight of the particles of the admixture may have an effective particle size in the range of 0.01 to 10 micrometers.
  • the finely divided admixture powder may be additionally mixed with an inert carrier such as a sugar having a larger particle size, for example, of up to 100 micrometers in diameter.
  • the composition may be pressurized using a compressed gas, such as nitrogen or a liquefied gas propellant.
  • a compressed gas such as nitrogen or a liquefied gas propellant.
  • the propellant may be chosen such that the compound and/or an admixture including the compound do not dissolve in the propellant to any substantial extent.
  • a pressurized form of the composition may also contain a surface-active agent.
  • the surface-active agent may be a liquid or solid non-ionic surface-active agent or may be a solid anionic surface-active agent, which in certain embodiments, may be in the form of a sodium salt.
  • compositions for rectal administration may be prepared by mixing the compounds or compositions of the disclosure with suitable non-irritating excipients or carriers such as for example, cocoa butter, polyethylene glycol or a suppository wax.
  • suitable non-irritating excipients or carriers such as for example, cocoa butter, polyethylene glycol or a suppository wax.
  • Such carriers may be solid at room temperature but liquid at body temperature and therefore melt in the rectum and release the drugs.
  • the compounds or compositions of the disclosure can be administered in the form of liposomes.
  • Liposomes are generally derived from phospholipids or other lipid substances that form mono- or multi-lamellar hydrated liquid crystals when dispersed in an aqueous medium. Any non-toxic, physiologically acceptable and metabolizable lipid capable of forming liposomes can be used, and in particular embodiments, the lipids utilized may be natural and/or synthetic phospholipids and phosphatidyl cholines (lecithins). Methods to form liposomes are known in the art (see, for example, Prescott, Ed., Meth. Cell Biol. 14:33 (1976), which is hereby incorporated by reference in its entirety).
  • Compositions including one or more compounds of the disclosure in liposome form can contain, for example, stabilizers, preservatives, excipients and the like.
  • methods of embodiments of the disclosure may include the step of administering or providing an "effective amount” or a "therapeutically effective amount” of a compound or composition of the disclosure to an individual.
  • an effective amount of the compounds of the disclosure may be any amount that produces the desired effect. As described above, this amount may vary depending on, for example, the circumstances under which the compound or composition is administered (e.g., to incite treatment or prophylactically), the type of individual, the size, health, etc. of the individual and so on.
  • the dosage may further vary based on the severity of the condition. For example, a higher dose may be administered to treat an individual with a well-developed
  • the dosage may be within the range of about 0.01 mg/kg body weight to about 10 mg/kg body weight.
  • the administration schedule may also vary. For example, in some embodiments
  • the compounds or compositions of the disclosure may be administered in a single dose once per day or once per week. In other embodiments, the compounds or compositions of the disclosure may be administered in one or two or more doses per day. For example, in one embodiment, an effective amount for a single day may be divided into separate dosages that may contain the same or a different amount of the compound or composition and may be administered several times throughout a single day. The dosage per administration and frequency of administration may depend, for example, on the specific compound or composition used, the condition being treated, the severity of the condition being treated, and the age, weight, and general physical condition of the individual to which the compound or composition is administered and other medications which the individual may be taking. In another exemplary embodiment, treatment may be initiated with smaller dosages that are less than the optimum dose of the compound, and the dosage may be increased incrementally until a more optimum dosage is achieved.
  • the compound administered can be provided as a pharmaceutical composition including compound as described above and a pharmaceutically acceptable excipient or a pure form of the compound may be administered.
  • the compound or composition of the disclosure may be used alone or in combination with one or more additional agents.
  • a compound or composition of disclosure may be formulated with one or more additional neuroprotective agents or combinations thereof such that the pharmaceutical composition obtained including the compound or composition of the disclosure and the one or more additional agents can be delivered to an individual in a single dose.
  • the compound or composition of the disclosure may be formulated as a separate pharmaceutical composition that is delivered in a separate dose from pharmaceutical compositions including the one or more additional agents.
  • two or more pharmaceutical compositions may be administered to deliver effective amounts of a compound or composition of the disclosure and the one or more additional agents.
  • glycopeptides related to PACAP produce PACi agonism, or VPACi agonism or VPAC 2 agonism, all of which may be useful feature for the treatment of neurodegeneration, particularly for PD or treatment of traumatic brain injury or stroke.
  • VPACi antagonism or VPAC 2 antagonism combined with PACi agonism may be particularly effective.
  • Results also show that glycosylation of PACAP peptides is a good strategy for increasing the in vivo stability and CNS penetration of peptide drugs, which may be useful as a strategy for the treatment of diseases like PD migraine, traumatic brain injury and stroke.
  • PACAP- VIP glycopeptides of the present invention have several significant advantages. For example, by binding selectively to PACi and VP AC receptors, the protein has a very narrow range of influence. Side effects are therefore minimized.
  • glycosylation allows the protein to cross the blood-brain barrier allowing the protein to carry out its function.
  • Glycopeptides of the invention can be used to treat one of the causes of ALS, PD, AD, HD migraines, traumatic brain injury, stroke and forms of dementia rather than just treating symptoms.
  • the protein has stronger effects than symptom -treating drugs.

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Abstract

La présente invention concerne une méthode de traitement d'une maladie neurodégénérative, d'une lésion cérébrale traumatique ou d'un accident vasculaire cérébral. En particulier, la présente invention concerne une méthode d'utilisation d'analogues PACAP/VIP d'un glycopeptide avec une meilleure pénétration du SNC pour le traitement d'une maladie neurodégénérative, d'une lésion cérébrale traumatique ou d'un accident vasculaire cérébral.
EP17753766.9A 2016-02-16 2017-02-15 Traitement de lésion cérébrale traumatique ou d'accident vasculaire cérébral Pending EP3416977A4 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US15/044,924 US10117907B2 (en) 2013-08-14 2016-02-16 Glycosylated PACAP/VIP analogues with enhanced CNS penetration for treatment of neurodegenerative diseases
PCT/US2017/017995 WO2017142961A1 (fr) 2016-02-16 2017-02-15 Traitement de lésion cérébrale traumatique ou d'accident vasculaire cérébral

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EP3416977A1 true EP3416977A1 (fr) 2018-12-26
EP3416977A4 EP3416977A4 (fr) 2019-07-17

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AR113022A1 (es) 2017-09-29 2020-01-15 Lilly Co Eli Anticuerpo anti-pacap

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CA2779496A1 (fr) * 2009-11-02 2011-05-05 The Administrators Of The Tulane Educational Fund Analogues de polypeptide d'activation d'adenylate cyclase hypophysaire (pacap) et procedes pour leur utilisation
WO2015023890A1 (fr) * 2013-08-14 2015-02-19 The Arizona Board Of Regents On Behalf Of The University Of Arizona Analogues de pacap/vip glycosylés avec pénétration du snc augmentée pour le traitement de maladies neurodégénératives
US10858410B2 (en) * 2015-08-12 2020-12-08 Arizona Board Of Regents On Behalf Of The University Of Arizona Glycosylated peptides with pseudoproline residues and having enhanced half-lives and ability to cross the blood brain barrier

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