Patent Grant
10662223
The present invention relates to a composition for organ, tissue or cell transplantation; a kit for organ, tissue or cell transplantation; or a method for organ, tissue or cell transplantation.
Organ transplantation is the transfer of tissue or an organ from an original site to another to replace damaged tissue or organ. The organ transplantation may have various problems, one of which is ischemic tissue injury due to ischemia-reperfusion (IR). The ischemic tissue injury caused by IR occurring in the organ transplantation results in delaying the recovery of renal function after the organ transplantation, which causes an inflammatory tissue reaction often serving as a prognostic factor that is bad for long-term maintenance of the function of the transplanted organ. Early IR injury incidentally occurring in the organ transplantation may lead to subsequent deterioration of the organ function and transplantation failure.
Particularly, lung transplantation is known as the sole therapeutic option for terminal lung diseases, and it is expected that patients' demands for lung transplantation will constantly increase. However, despite steady medical advancement, lung transplantation survivability is still not higher than other organs. The most frequently occurring problem at the early stage after a lung transplant is graft dysfunction, one cause of which is an IR injury.
Meanwhile, a flap is a piece of skin or tissue with a pedicle or tissue similar thereto, which is transferred from one site to another site of the body, the transferred tissue capable of surviving in the pedicle or tissue similar thereto. Flap surgery is a surgery technique that is most widely used in plastic and reconstructive surgeries for soft tissue defects or chronic wounds, which cannot be dealt with through skin transplantation, and useful for reconstructing an appearance and lost function, and particularly, the flap surgery can rapidly restore the defects or wounds by a primary reconstruction through transplantation of a combination of various types of tissue such as bones, tendons, muscles, and nerves. In the flap surgery, flap survivability is closely related to an IR injury treatment. Therefore, it is expected that a method for stably enhancing the flap survivability through the IR injury treatment will be very useful.
Also, cell transplantation, similarly to organ or tissue transplantation, is carried out to treat a disease, and as a representative example, transplantation of cells in the islets of Langerhans for improving type 1 diabetes may be used. Within the first week of the transplantation of the islets of Langerhans, most of the grafts are lost, which may be because they are exposed to various stress factors such as hypoxia, and to proinflammatory cytokines and free radicals before secondary angiogenesis after the transplantation.
An object of the present invention is directed to promoting survivability and/or functions of organs, tissue and individual cell grafts.
Another object of the present invention is directed to strengthening the survivability and/or function of an organ, tissue or cell graft after transplantation.
Still another object of the present invention is directed to providing a method and/or composition for temporarily storing an organ, tissue or cells without damage.
In one aspect, the present invention provides a composition for organ, tissue or cell transplantation, which comprises, as an active ingredient, a peptide comprising the amino acid sequence of SEQ ID NO: 1, a peptide having at least 80% sequence homology with the amino acid sequence or a fragment thereof. In the composition, the fragment may be a fragment composed of three or more amino acids.
In one aspect, the composition may be administered to a donor and/or recipient.
In one aspect, the composition may be administered in at least one stage before, during and after transplantation.
In another aspect, the composition may be to store an organ, tissue or cells isolated from a donor.
In one aspect, the composition may comprise the peptide as the active ingredient at a sufficient amount for strengthening the survivability or function of an organ, tissue or cell after being transplanted to a recipient.
In one aspect, the composition may comprise the peptide as the active ingredient at a concentration of 10 to 1000 mg/L with respect to the total volume of the composition.
In one aspect, the composition may comprise the peptide as the active ingredient at a concentration of 50 to 500 mg/L with respect to the total volume of the composition.
In one aspect, the present invention may provide a kit for organ, tissue or cell transplantation, comprising a composition for organ, tissue or cell transplantation; and a protocol including a method for using the composition.
In one aspect, in the kit, the composition may be at least one of a composition administered to a donor before transplantation; a composition administered to a recipient before transplantation; a composition administered to a donor during transplantation; a composition administered to a recipient during transplantation; a composition for storing organ, tissue or cells isolated from a donor; a composition administered to a donor after transplantation; and a composition administered to a recipient after transplantation.
In another aspect, in the kit, the protocol may include doses, administration methods and administration intervals for the respective compositions.
In the kit according to another aspect, the protocol may include the administration of the composition through perfusion of an organ, tissue or cells in a donor's or recipient's body with the organ, tissue or cells present in the body.
In another aspect, the present invention may provide a method for organ, tissue or cell transplantation, which comprises treating an isolated organ, tissue or cells with at least one of the above-described compositions for organ, tissue or cell transplantation, or administering at least one of the above-described compositions for organ, tissue or cell transplantation to a donor and/or recipient for the organ, tissue or cell transplantation.
In another aspect, the method may comprise at least one of administration of the composition to a donor before transplantation; administration of the composition to a recipient before transplantation; administration of the composition to a donor during transplantation; administration of the composition to a recipient during transplantation; storage of an organ, tissue or cells isolated from a donor in the composition; administration of the composition to a recipient after transplantation; and administration of the composition to a donor after transplantation.
In one aspect, the method may comprise administering the composition by perfusing an organ, tissue or cells in a donor's or recipient's body with the organ, tissue or cells present in the body.
In another aspect, the composition may be treated or administered at a single dose of 1 to 10000 mg based on a 60-kg adult.
In another aspect, the composition may be treated or administered at a single dose of 200 to 5000 mg based on a 60-kg adult.
In one aspect, the present invention may provide a use of at least one of the above-described compositions to treat an isolated organ, tissue or cells, or to be administered to a donor and/or recipient of organ, tissue or cell transplantation.
In one aspect, the present invention can promote the survivability and/or functions of organ, tissue, and individual cell grafts.
In another aspect, the present invention can strengthen the survivability and/or function after organ, tissue or cell transplantation.
In still another aspect, the present invention can temporarily store an organ, tissue or cells without damage.
The present invention may be modified in various forms and have many examples, and thus will be described in detail based on the examples below. However, these examples are not provided to limit the present invention to specific embodiments, and it should be understood that the present invention can have various examples and applications as described in the claims, and comprises all modifications, equivalents and alternatives within the spirit and technical scope of the present invention. To explain the present invention, if it is determined that a detailed description of related art may obscure the gist of the present invention, the detailed description will be omitted.
Telomere, which is a repetitive genetic material located at each terminus of a chromosome, is known to prevent damage in a corresponding chromosome or coupling to a different chromosome. The telomere is gradually shortened with cell divisions, becoming very short after a certain number of cell divisions, and the cell eventually stops being divided and dies. On the other hand, the elongation of telomeres is known to extend the life span of a cell. As an example, it has been known that, in cancer cells, an enzyme called telomerase is secreted to prevent the shortening of telomeres, resulting in steady proliferation of the cancer cells, without death. In one aspect, the present invention relates to a composition or kit, which is used to treat a donor, recipient, organ, tissue, the cluster of cells and/or each cell in any step of extraction, storage and transplantation of an organ, tissue or cells. The organ, tissue the cluster of cells or each cell may be extracted from a donor, treated with the composition disclosed in the specification, and transplanted into a recipient. In another aspect, in addition to the above-described method, the organ, tissue the cluster of cells or each cell may be treated in a donor's body while present in the body. Selectively, the organ is reperfused with the composition disclosed in the specification, for example, a recipient's blood before, during and/or after a surgery. Also, the composition disclosed the specification may be administered to a donor before or during extraction of an organ, tissue, cluster of cells or each cell.
In one aspect of the present invention, a peptide of SEQ ID NO: 1, a fragment of the peptide of SEQ ID NO: 1 or a peptide having at least 80% sequence homology with the peptide sequence comprises telomerase, specifically, a peptide derived from Homo sapiens telomerase.
The peptide set forth in SEQ ID NO: 1 is shown in Table 1 below. The “name” in Table 1 below is given to distinguish one peptide to another. In one aspect of the present invention, the peptide set forth in SEQ ID NO: 1 represents the whole peptide of Homo sapiens telomerase. In another aspect of the present invention, the peptide comprising the sequence of SEQ ID NO: 1, the fragment of the peptide comprising the sequence of SEQ ID NO: 1 or the peptide having at least 80% sequence homology with the peptide sequence includes a “synthetic peptide” synthesized from a peptide present at a corresponding location of the peptides included in the telomerase. SEQ. ID. NO: 2 denotes the full-length amino acid sequence of the telomerase.
The peptide disclosed in the specification may include a peptide having 80% or higher, 85% or higher, 90% or higher, 95% or higher, 96% or higher, 97% or higher, 98% or higher, or 99% or higher sequence homology. Also, the peptide disclosed in the specification may include a peptide having at least one, two, three, four, five, six, or seven different amino acids from the peptide of SEQ ID NO: 1 or a fragment thereof.
In one aspect of the present invention, the amino acid change is one of the properties that change physicochemical characteristics of the peptide. For example, amino acids may be changed to enhance thermal stability, change substrate specificity, and shift an optimal pH of the peptide.
The term “amino acid” used herein not only includes the 22 standard amino acids that are naturally integrated into a peptide, but also includes the D-isomers and transformed amino acids. Therefore, in one aspect of the present invention, the peptide may be a peptide including a D-amino acid. On the other hand, in another aspect of the present invention, the peptide may include a non-standard amino acid, which is subjected to post-translational modification. Examples of the post-translational modification include phosphorylation, glycosylation, acylation (including acetylation, myristorylation, and palmitoylation), alkylation, carboxylation, hydroxylation, glycation, biotinylation, ubiquitinylation, a change in chemical properties (e.g. β-removing deimidation, deamidation), and a structural change (e.g. formation of a disulfide bridge). The post-translational modification also includes changes of amino acids occurring due to chemical reactions during coupling with crosslinkers for formation of a peptide conjugate, for example, a change in an amino acid such as a change in an amino group, a carboxyl group, or a side chain.
The peptide disclosed herein may be a wild-type peptide identified and isolated from a natural source. Meanwhile, the peptide disclosed in the specification may be an artificial variant comprising an amino acid sequence in which one or more amino acids are substituted, deleted, and/or inserted compared with the fragments of the peptide of SEQ. ID. NO: 1. The changing of amino acids in the wild-type polypeptide, as well as the artificial variant, includes substitutions of conservative amino acids, which does not have a significant influence on folding and/or activity of a protein. The conservative substitution may be carried out within the range of the group consisting of basic amino acids (arginine, lysine and histidine), acidic amino acid (glutamic acid and aspartic acid), polar amino acids (glutamine and asparagine), hydrophobic amino acids (leucine, isoleucine, valine and methionine), aromatic amino acids (phenylalanine, tryptophan and tyrosine), and small amino acids (glycine, alanine, serine and threonine). Generally, amino acid substitutions that do not change specific activities are known in the art. The most frequently-occurring exchange takes place between Ala/Ser, Val/Ile, Asp/Glu, Thr/Ser, Ala/Gly, Ala/Thr, Ser/Asn, Ala/Val, Ser/Gly, Tyr/Phe, Ala/Pro, Lys/Arg, Asp/Asn, Leu/Ile, Leu/Val, Ala/Glu, and Asp/Gly, and vice versa. Other examples of the conservative substitution are shown in Table 2 below.
In terms of biological properties of the peptide, a substantial modification is performed by selecting a substitution part which has a considerably different effect in (a) maintaining the backbone structure, for example, a sheet- or helix-like three-dimensional structure, of the polypeptide in the substituted region, (b) maintaining charge or hydrophobicity of the molecule at a target site, or (c) maintaining the bulk of a side chain. Natural residues are classified into the following groups, based on general properties of the side chain:
(1) Hydrophobic: norleucine, met, ala, val, leu, ile;
(2) Neutral hydrophilic: cys, ser, thr;
(3) Acidic: asp, glu;
(4) Basic: asn, gin, his, lys, arg;
(5) Residues affecting chain conformation: gly, pro; and
(6) Aromatic: trp, tyr, phe.
Non-conservative substitutions may be performed by exchanging a member of one of the groups to that of another group. Any cysteine residue, which is not associated with maintaining the proper three-dimensional structure of the peptide, may typically be substituted into serine, thus increasing the oxidative stability of the molecule and preventing improper crosslinks, and, conversely, enhanced stability can be achieved by adding cysteine bond(s) to the peptide.
A different type of amino acid variant of the peptide is made by changing a glycosylation pattern of an antibody. The term “change” used herein refers to deletion of one or more carbohydrate residues that are found on the peptide and/or addition of one or more glycosylation sites which do not exist in the peptide.
Glycosylation in peptides are typically N- or O-linked glycosylation. The term “N linked glycosylation” used herein refers to attachment of carbohydrate residues to side chains of asparagine residues. As tripeptide sequences, asparagine-X-serine and asparagine-X-threonine (where the X is any amino acid, excluding proline) are recognition sequences for enzymatically attaching a carbohydrate residue to a side chain of an asparagine. Therefore, when one of these tripeptide sequences is present in a polypeptide, a potential glycosylation site is created. The “O-linked glycosylation” used herein refers to the attachment of one of the saccharides, for example, N-acetylgalactosamine, galactose, or xylose, to hydroxyamino acids and, most typically, to serine or threonine, but 5-hydroxyproline or 5-hydroxylysine may also be used.
Addition of a glycosylation site to the peptide is conveniently performed by changing the amino acid sequence to contain the tripeptide sequence described above (for an N-linked glycosylation site). Such a change may be made by addition of one or more serine or threonine residues to the first antibody sequence or substitution of the first antibody sequence with one or more serine or threonine residues (for an O-linked glycosylation site).
The term “cells” used herein refers to a random type of animal cells such as animal cells suitable for transplantation. The cells may be generally primary cells obtained from an animal donor, secondary cells from an established cell line or equivalent cells thereof. These cells are transfected in vitro by an expression vector that selectively changes a function of the cells in a certain method. The cells include, not in a limiting manner, for example, cells in the islets of Langerhans, such as cells that are a part of the pancreatic islets of Langerhans, liver cells, fibroblasts, bone marrow cells, myocytes and stem cells, and cells in the central nerve system such as the spinal cord (e.g., nerve cells). Throughout the specification, the “cell(s) in the islets of Langerhans” is a general term used to describe the cluster of cells present in the pancreas, known as the islet, for example, the islets of Langerhans. In the islets of Langerhans, several types of cells, for example, n-cells (insulin production), α-cells (glucagon production), v-cells (somatostatin production), F cells (pancreatic polypeptide production), enterochromaffin cells (serotonin production), PP cells and Dl cells are included. The term “stem cells” is a known term in the art referring to cells that have an ability to be indefinitely divided in a culture medium to become differentiated cells. The stem cells include, for example, totipotent, pluripotent, multipotent and unipotent stem cells, such as neuronal cells, liver cells, myocytes, and hematopoietic progenitor cells.
The term “organ” used herein is a general term used to describe any anatomical part or member having a specific function in an animal throughout the specification. Also, the organ includes, for example, a part corresponding to the organ such as cohesion tissue obtained from the organ. Such an organ unlimitedly includes the kidney, the liver, the heart, the stomach, the intestine such as a large or small intestine, the pancreas, the skin and the lung. The organ also includes the bone, skeletal muscles, abdominal muscles, limbs, the mesentery, and blood vessels such as an aortic transplant.
The term “transplantation” used herein is a general term used to describe a process of transplanting an organ, tissue, a cluster of cells, or an individual cell into a patient. The term “transplantation” used herein refers to a process of delivering surviving tissue or cells from a donor to a recipient to maintain functional integrity of the tissue or cells transplanted into the recipient.
The “administration during transplantation” used herein refers to administration in the entire process of a transplantation surgery. That is, the administration during transplantation includes the administration right after the extraction of an organ, tissue, or cell from a donor, during the surgery for transplanting the extracted organ, tissue, or cell into a recipient, and right after the transplant.
The “administration before transplantation” used herein includes administration of the composition disclosed in the specification to a donor and/or a recipient several minutes, hours, days, or tens of days before a surgery as a preparation step for a transplantation surgery.
The “administration after transplantation” used herein includes the administration of the composition disclosed in the specification to a recipient several minutes, hours, days, tens of days, hundreds of days after a surgery as a maintenance step of a transplantation surgery.
In the present invention, the “ischemic injury” refers to a fatal injury occurring as a result of interruption of blood circulation and thus reduction of oxygen transfer in an organ requiring blood supply, such as the heart, brain, kidney and lung, leading to a dysfunction of tissue and apoptosis. The cause of such an ischemic injury includes, but is not limited to, a vascular disease, coronary thrombosis, cerebrovascular thrombosis, aneurysm rupture, systemic hemorrhage, a crush injury, sepsis, severe skin burn, vascular ligation surgery (e.g., spinal ischemia during thoracoabdominal aneurysm surgery), cardiopulmonary bypass, organ transplantation, cardiopulmonary collapse (sudden cardiac death), suffocation.
Also, the “ischemic injury” according to the present invention includes an IR injury that can be caused by organ transplantation, other than ischemic injury that can conventionally occur. The IR injury includes cerebrovascular ischemic-reperfusion injury, renal ischemic-reperfusion injury, hepatic ischemic-reperfusion injury, ischemic-reperfusion cardiomyopathy, ischemic-reperfusion skin injury, gastrointestinal ischemic-reperfusion injury, intestinal ischemic-reperfusion injury, gastric ischemic-reperfusion injury, ischemic-reperfusion lung injury, pancreatic ischemic-reperfusion injury, ischemic-reperfusion skeletal muscle injury, ischemic-reperfusion abdominal muscle injury, ischemic-reperfusion limb injury, ischemic-reperfusion colitis, mesenteric ischemic-reperfusion injury, and asymptomatic ischemic-reperfusion injury but is not limited thereto.
The IR injury may frequently occur during organ transplantation surgery. For example, it is known that gradual functional loss and a dysfunction of a transplanted kidney are associated with the IR injury in renal transplantation, and the activation of the innate immune system by the IR tissue injury is one of the important causes.
In one aspect, the present invention provides a transplantation method, which comprises: administering the peptide-containing composition into a transplant donor; obtaining an organ, tissue or cells from the donor; and transplanting the obtained organ, tissue or cells into a recipient. In this method, an amount of the peptide administered into the donor is an amount sufficient for strengthening the survivability or function of an organ, tissue or cell after being transplanted into the recipient. Here, the administration to the donor may be continuously performed during or right before a surgery and in the preparation step before the surgery and/or the maintenance step after the surgery. The donor may be a surviving donor, brain dead donor, or a donor before or after brain death.
In another aspect, the present invention provides a transplantation method, which comprises: obtaining an organ, tissue or cells from a donor; maintaining the obtained organ, tissue or cells in a composition containing the peptide; and transplanting the stored organ, tissue or cells into a recipient. In this method, an amount of the peptide in the composition for storing the organ, tissue or cells is an amount that is sufficient for strengthening the survivability or function of the organ, tissue or cells transplanted into the recipient.
In another aspect, the present invention provides a transplantation method, which comprises: obtaining an organ, tissue or cells from a donor transplanting the obtained organ, tissue or cells into a recipient; and administering the composition containing the peptide into the recipient. In this method, an amount of the peptide administered to the recipient is an amount that is sufficient for strengthening the survivability or function of the organ, tissue or cells after being transplanted into the recipient. Here, the administration to the recipient may be continuously performed during or right after the surgery, and in a maintenance step after the surgery.
In one embodiment, the composition disclosed in the specification may be administered to a recipient within 0 to 20 days, for example, 1, 2, 4, 6, 8, 10, 12, 14, 18, or 20 days, after transplanting an organ, tissue or cells into the recipient. In another embodiment, the composition disclosed in the specification may be administered to a recipient at least once, for example, several times or continuously, from day 21 after transplanting the organ, tissue or cells into the recipient for a long time as long as needed for ensuring the survival of the transplant. The composition disclosed in the specification may be administered to the recipient in a suitable form determined whether rejection of the transplanted organ, tissue or cells is exhibited, for example, chronic or acute rejection.
In one aspect, the composition comprising the peptide may be administered to both of a donor and a recipient. In another aspect, the composition comprising the peptide may be administered to a donor and/or recipient, and during the transplantation, an organ, tissue or cells may be temporarily stored in the composition comprising the peptide.
In one embodiment, the composition disclosed in the specification may be administered by perfusing an organ, tissue or cells in a donor's or recipient's body with the organ, tissue or cells present in the body.
In the method described in the specification, the organ, tissue or cell may be any organ, tissue or cell which may be transplanted. For example, the organ may be the liver, kidney, heart, pancreas, lung, small intestine and/or skin, and tissue or cells thereof.
The donor may be heterologous or homologous to the recipient. Both the donor and recipient may be animals except humans, or humans. Also, the donor may be an animal excluding a human, for example, a pig, or the recipient may be a human. In one embodiment, the tissue or cells may be own tissue or cells of the recipient. In other words, the donor and the recipient may be the same individual.
The composition disclosed in the specification may comprise the peptide as an active ingredient in combination with another active ingredient. For example, the peptide disclosed in the specification may be added to PERFADEX™ (a lightly buffered colloid-based electrolyte preservation solution for rapid cooling, perfusion and storage of organs in connection with transplantation manufacture by XVIVO Perfusion AB), which is commercially available as a lung preservation solution.
In the composition disclosed in the specification, a concentration of the peptide may be conventionally determined as known in the art. For example, the composition according to one aspect of the present invention may comprise the peptide comprising the amino acid sequence of SEQ ID NO: 1, a peptide having at least 80% sequence homology with the amino acid sequence or a fragment thereof at a content of 10 to 1000 mg/L, specifically, 50 to 500 mg/L, and more specifically, 30 to 200 mg/L, but if there is a difference in content-based effect, the content may be suitably adjusted. In another aspect, the composition may comprise the peptide at 1 mg/L or more, 5 mg/L or more, 10 mg/L or more, 20 mg/L or more, 30 mg/L or more, 40 mg/L or more, 50 mg/L or more, 60 mg/L or more, 70 mg/L or more, 80 mg/L or more, or 90 mg/L or more. Also, the composition may comprise the peptide at 50000 mg/L or less, 40000 mg/L or less, 30000 mg/L or less, 200000 mg/L or less, 10000 mg/L or less, 8000 mg/L or less, 6000 mg/L or less, 4000 mg/L or less, 2000 mg/L or less, 1000 mg/L or less, 900 mg/L or less, 800 mg/L or less, 700 mg/L or less, 600 mg/L or less, or 500 mg/L or less. When the composition includes the peptide in the above range or below, it is suitable for exhibiting an effect intended by the present invention and is able to satisfy both stability and safety of the composition. Moreover, the above range may be appropriate in terms of cost-effectiveness.
In the specification, the dose, administration method, and administration cycle of the peptide are widely known in the art, and thus the peptide may be administered according to the standards known in the art depending on the conditions of each patient. A specific dose may be determined by one of ordinary skill in the art, and a daily dose of the peptide may be, specifically, 1 μg/kg/day to 10 g/kg/day, more specifically, 10 μg/kg/day to 100 mg/kg/day, and further more specifically, 50 μg/kg/day to 50 mg/kg/day, but not limited thereto, and may be changed according to various parameters such as age of a subject for administration, a health condition, and complications. For example, the peptide may be locally or intradermally administered into a corresponding site. Daily doses administered right before, during, and right after transplantation may be 1 mg to 10000 mg based on a 60-kg adult. In another aspect, a dose may be 1 mg or more, 5 mg or more, 10 mg or more, 50 mg or more, 100 mg or more, 200 mg or more, 300 mg or more, 400 mg or more, 500 mg or more, 600 mg or more, 700 mg or more, 800 mg or more, 900 mg or more, or 950 mg or more. In another aspect, the dose may be 10000 mg or less, 9000 mg or less, 8000 mg or less, 7000 mg or less, 6000 mg or less, 5000 mg or less, 4000 mg or less, 3000 mg or less, 2000 mg or less, or 1500 mg or less. In the maintenance step after transplantation, the administration may be performed at least once a day for several days, and the time interval may be increased. For example, the administration may be performed at the 1st, 2th, 3th, and 4th weeks, and then performed at the 6th and 10th weeks.
An organ, tissue, a cluster of cells, and/or isolated cells may be extracted from a donor, and transplanted by any method known in the art (the example of the reference document: Oxford Textbook of Surgery, Morris and Malt, Eds., Oxford University Press (1994)). It may be known to those of ordinary skill in the art that extraction and transplantation methods may be changed according to a variety of environments, for example, a type of the organ, tissue, or cell and a type of donor.
The composition disclosed in the specification may be in a solution prepared by dissolving the peptide in a solvent. The solvent may be any one that can be used in the body, for example, a saline, an aqueous solution or a buffer, without limitation. In one aspect, the composition may be a solution that is prepared by adding the peptide disclosed in the specification to any liquid known in the art (the example of the reference document: Oxford Textbook of Surgery, Morris and Malt, Eds., Oxford University Press, 1994), which is suitable for being administered to a patient, or a liquid suitable for maintaining an organ, tissue or cells in vitro. Generally, the liquid may be an aqueous solution. Examples of the solutions may include phosphate buffered saline (PBS), CELSIOR™ solution (a liquid composition for perfusion, reperfusion and preservations of organs manufactured by Institut Georges Lopez, SALR), PERFADEX™ (a lightly buffered colloid-based electrolyte preservation solution for rapid cooling, perfusion and storage of organs in connection with transplantation manufacture by XVIVO Perfusion AB), Collins' solution, citrate solution, and UNIVERSITY OF WISCONSIN™ (UW) solution (a transplantation solution with the composition of 100 mM potassium lactobionate, 25 mM KH2PO4, 5 mM MgSO4, 30 mM raffinose, 5 mM adenosine, 3 mM glutathione, 1 mM allopurinol, and 50 g/L Hydroxyethyl starch) (Oxford Textbook of Surgery, Morris and Malt, Eds., Oxford University Press, 1994).
One known transplantation solution is the UW solution, which may contain: KH2PO5 (25 mmol/L), MgSO4 (5 mmol/L), raffinose (30 mmol/L), hydroxyethyl pentafraction starch (50/L), penicillin (200,000 U/L), insulin (40 U/L), dexamethasone (16 mg/dL), K lactobionate (100 mmol/L), glutathione-stimulating hormone (3 mmol/L), adenosine (5 mmol/L), allopurinol (1 mmol/L), Na (25 mmol/L), and K (125 mmol/L).
Another known transplantation solution is a pay-Collins' solution, which may contain: sodium (10 mM), chloride (15 mM), potassium (115 mM), bicarbonate (10 mM), phosphate (50 mM) and glucose (195 mM).
In one aspect of the present invention, a composition for treating and preventing ischemic injury, which comprises a peptide comprising an amino acid sequence of SEQ ID NO: 1, a peptide having at least 80% sequence homology with the amino acid sequence or a fragment thereof as an active ingredient.
The composition according to an aspect of the present invention is a composition administered to a donor and/or recipient in a preparation step before transplantation or a composition administered to a donor and/or recipient in a maintenance step after transplantation, which may comprise a peptide comprising an amino acid sequence of SEQ ID NO: 1, a peptide having at least 80% sequence homology with the amino acid sequence or a fragment thereof at a content of 0.1 μg/mg to 1 mg/mg, specifically, 1 μg/mg to 0.5 mg/mg, and more specifically, 10 μg/mg to 0.1 mg/mg. Within the above range, the composition may be suitable for exhibiting a desired effect of the present invention, may satisfy both stability and safety of the composition, and may be suitable in terms of cost-effectiveness.
The composition according to an aspect of the present invention may be applied to all animals including a human, a dog, a chicken, a pig, a cow, a sheep, a guinea pig, and a monkey.
The composition according to an aspect of the present invention may be a pharmaceutical composition for treating and preventing IR injury, which comprises a peptide comprising an amino acid sequence of SEQ ID NO: 1, a peptide having at least 80% sequence homology with the amino acid sequence or a fragment thereof as an active ingredient. The pharmaceutical composition according to an aspect of the present invention may be orally, intrarectally, transdermally, intravenously, intramuscularly, intraperitoneally, bone marrow, intrathecally, or subcutaneously administered.
Forms for oral administration may be, but are not limited to, tablets, pills, soft or hard capsules, granules, powders, solution, or emulsion. Forms of non-oral administration can be, but not limited to, an injection, drip, lotion, ointment, gel, cream, suspension, emulsion, suppository, patch or spray.
The pharmaceutical composition according to one aspect of the present invention may comprise, as needed, additives, such as diluents, excipients, lubricants, binders, disintegrants, buffers, dispersants, surfactants, coloring agents, aromatics, or sweeteners. The pharmaceutical composition according to one aspect of the present invention may be prepared by a conventional method in the art.
The active ingredient of the pharmaceutical composition according to an aspect of the present invention may vary according to the patient's age, sex, weight, pathology and state, administration route, or prescriber's judgment. Dosage based on such factors may be determined within levels of those of ordinary skill in the an, and a daily dose of the composition administered into a donor and/or recipient in the preparation step before transplantation or the composition administered to a donor and/or recipient in the maintenance step after transplantation may be, for example, 0.1 μg/kg/day to 1 g/kg/day, specifically, 1 μg/kg/day to 10 mg/kg/day, more specifically, 10 μg/kg/day to 1 mg/kg/day, and further more specifically, 50 μg/kg/day to 100 μg/kg/day, but the present invention is not limited thereto. The pharmaceutical composition according to an aspect of the present invention may be administered one to three times a day, but the present invention is not limited thereto.
The composition according to an aspect of the present invention may be a food composition for treating and preventing an IR injury, which comprises a peptide comprising an amino acid sequence of SEQ ID NO: 1, a peptide having at least 80% sequence homology with the amino acid sequence or a fragment thereof as an active ingredient.
The food composition according to one aspect of the present invention may be formulated in the form of, for example, tablets, granules, powder, liquid, and solid, but the present invention is not particularly limited thereto. Each form may be prepared by mixing components conventionally used in the corresponding field as well as the active ingredient according to the form or the purpose of use without difficulty and may produce a synergic effect in combination with other ingredients.
The terms used in the specification are intended to be used to describe specific embodiments, not to limit the present invention. Terms without numbers ahead are not to limit the quantity but to represent the existence of at least one article cited herein. The terms “comprising,” “having,” “including” and “containing” should be interpreted openly (i.e. “including but not limited to”).
Mention of a numerical range replaces mention of individual numbers within the range, and unless cited otherwise, each number is applied to the specification as individually mentioned in the specification. The end values of all the ranges are included in the range and can be combined individually.
All methods mentioned in the specification may be performed in suitable order unless noted otherwise or explicitly contradicted with the context. The use of any one embodiment and all embodiments, or exemplary language (e.g., “such as”, “like ˜”), unless included in the claims, is used to more clearly describe the present invention, not to limit the scope of the present invention. Any language herein outside of the claims should not be interpreted as necessary for the present invention. Unless defined otherwise, technical and scientific terms used herein have meanings ordinarily understood by those of ordinary skill in the art to which the present invention belongs.
The exemplary embodiments of the present invention include the best mode known to the inventors to perform the present invention. Variations in the exemplary embodiments can become clear to those skilled in the art when reading the descriptions above. It is expected that the inventors suitably use such variations, and embody the present invention by different methods described in the specification. Thus, the present invention, as allowed by the patent law, includes equivalents and all modifications of the gist of the present invention mentioned in the accompanying claims. Moreover, all possible variations with any combination of the above-mentioned components are included in the present invention, unless explicitly stated otherwise or contradicting the context. Although the present invention is described and shown by exemplary embodiments, those skilled in the art will understand well that there can be various changes in the form and details without departing from the spirit of the invention and range, defined by the claims below.
In the following examples, the effects of inhibiting renal injury and enhancing flap survivability were examined by administering the peptide having the sequence set forth in SEQ ID NO: 1 (PEP 1) in IR injuries occurring at the kidney, lung, rectus abdominis flaps, thereby confirming the effects of the peptide on prevention and treatment of an ischemic injury.
Hereinafter, the configuration and effects of the present invention will be described in further detail with reference to examples and experimental examples. However, the following examples and experimental examples are merely provided to illustrate the present invention to help understanding the present invention, and the scope of the present invention is not limited thereto.
The peptide of SEQ ID NO: 1 (hereinafter, referred to as “PEP 1”) was prepared according to a conventionally known method of solid phase peptide synthesis. Specifically, the peptide was synthesized by coupling each amino acid from the C-terminus through Fmoc solid phase peptide synthesis (SPPS) using ASP48S (Peptron, Inc., Daejeon, Korea). Peptides in which the first amino acid at the C-terminus is attached to the resin were used as follows:
NH2-Lys(Boc)-2-chloro-Trityl Resin
NH2-Ala-2-chloro-Trityl Resin
NH2-Arg(Pbf)-2-chloro-Trityl Resin
In all amino acid ingredients used to synthesize the peptide, the N-term was protected with Fmoc, and the residues were protected with Trt, Boc, t-butylester (t-Bu), and 2,2,4,6,7-pentamethyl dihydro-benzofuran-5-sulfonyl (Pbf) that can be removed from an acid. Examples of the amino acids are as follows:
Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Pro-OH, Fmoc-Leu-OH, Fmoc-ile-OH, Fmoc-Phe-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Met-OH, Fmoc-Asn(Trt)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Ahx-OH, Trt-Mercaptoacetic acid.
As a coupling reagent, 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetamethylaminium hexafluorophosphate (HBTU)/N-Hydroxybenzotriazole (HOBt)/4-Methylmorpholine (NMM) was used. Fmoc deprotection was carried out using piperidine in 20% DMF. To isolate the synthesized peptide from the resin and remove the protective group of the residue, a cleavage cocktail [trifluoroacetic acid (TFA) triisopropylsilane (TIS)/ethanedithiol (EDT)/H2O=92.5/2.5/2.5/2.5] was used.
Each peptide was synthesized by a repeated process of reacting each of corresponding amino acids to the starting amino acid protected by the amino acid protective group while binding to a solid phase scaffold, washing the resulting product with a solvent, and performing deprotection. After being detached from the resin, the synthesized peptide was purified by HPLC, coupling validated by mass spectrometry (MS), and lyophilized.
The purity of all peptides used in the embodiment was 95% or higher by high-performance liquid chromatography.
A specific process for preparing the peptide PEP1 according to the present invention will be described as follows:
1) Coupling
The amino acid (8 equivalents) protected with NH2-Lys(Boc)-2-chloro-trityl resin, and a coupling reagent [HBTU (8 equivalents)/HOBt (8 equivalents)/NMM (16 equivalents)] melted in DMF were mixed together and incubated at room temperature for 2 hours. The resulting product was sequentially washed with DMF, MeOH, and DMF.
2) Fmoc Deprotection
Piperidine in 20% DMF was added to the resulting product, and the mixture was incubated twice at room temperature for 5 minutes and then sequentially washed with DMF, MeOH and DMF.
3) The peptide backbone [NH2-E(OtBu)-A-R(Pbf)-P-A-L-L-T(tBu)-S(tBu)-R(Pbf)L-R(Pbf)-F-I-P-K(Boc)-2-chloro-Trityl Resin] was prepared by repeating reactions 1 and 2.
4) Cleavage: The peptide was isolated from the resin by adding the cleavage cocktail.
5) After adding cooling diethyl ether to the obtained mixture, a peptide obtained by centrifugation was precipitated.
6) Following purification by Prep-HPLC, a resulting product was analyzed by LC/MS to identify a molecular weight, and lyophilized to prepare a powder.
Kidney IR which may occur in renal transplantation was induced as follows for observing the effect of PEP1.
A renal JR injury mouse model was obtained by inducing IR by bilateral clamping renal pedicles for 30 minutes and restoring blood flow after 30 minutes by removing the clamps. Experimental groups were divided into three groups, which are an administered group (PEP 1), a control group (PBS: without PEP 1 administration), and a Sham group (no bilateral clamping). PEP 1 was subcutaneously injected at a concentration of 1000 nmol/kg 30 minutes before and 12 hours after the IR induction.
A C57BL/6 mouse (8-week-old; Charles River Laboratories, Wilmington, Mass.) was used to induce renal IR injury. The renal pedicles were clamped with vascular forceps to block blood flow, and ischemia was induced for 28 hours in the renal IR injury model, followed by reperfusion.
The peptide PEP 1 was diluted with PBS to a concentration of 1000 nmol/kg, and then intraperitoneally injected twice, 30 minutes before and 12 hours after the IR. The experiment was conducted by dividing experimental groups into the administered group (PEP 1), the control group (PBS), and the Sham group (the group without renal injury as the group in which IR injury does not occur).
Blood was taken 24 hours after the JR and the levels of blood urea nitrogen (BUN) and creatine as renal toxicity markers were measured, renal tissue was taken and prepared into paraffin blocks for immunohistochemical and histological studies, and then proteins were extracted to measure cytokine levels. The creatine concentration and BUN were measured using an autoanalyzer (Technicon RA-1000; Bayer, Tarrytown, N.Y.).
As a result, the PEP 1-administered group showed significantly decreased BUN and creatine levels, compared with the PBS control group (refer to
Renal tissue was stained with periodic-acid-Schiff (PAS) according to the protocol of the manufacturer (Polysciences, Inc., Warrington, Pa., USA) 24 hours after the IR. After the staining, renal tissue injury was evaluated through renal tissue injury scoring. The PEP 1-administered group showed remarkably increased renal tissue injury, compared with the PBS control group (refer to
Renal apoptosis was evaluated by staining renal tissue with TUNEL stain 24 hours after the IR. Renal paraffin sections were stained with TUNEL using a TUNEL staining kit (Roche Applied Science, Indianapolis, Ind., USA).
As a result, the PEP 1-administered group showed remarkably decreased TUNEL-positive cells, compared with the PBS control group, indicating that PEP 1 inhibits renal tissue apoptosis (refer to
Infiltration of innate immune cells was evaluated by staining the renal tissue with a macrophage maker (F4/80) and a neutrophil maker (Gr-1) through immunohistochemistry 24 hours after the IR. Specifically, infiltrated macrophages and neutrophils were stained with a macrophage-specific antibody (F4/80, abcam., Cambridge, Mass.) by an immunochemical method performed on paraffin-containing sections.
The PEP 1-administered group showed remarkably decreased infiltration of macrophages and neutrophils into renal tissue, compared with the PBS control group (refer to
Protein was extracted from renal tissue 24 hours after the IR, and IL-6, MCP-1 and TNF-α levels were measured by a cytometric bead array. Mouse IL-6, MCP-1, TNF-α, and an ELISA kit were purchased from R&D Systems, and the experiment was conducted according to the manufacturer's protocol.
As a result, the PEP 1-administered group showed significantly decreased IL-6 and MCP-1 levels, compared with the PBS control group, but no significant difference in TNF-α level was observed (refer to
As described above, the effect of PEP 1 on protecting the renal IR injury was evaluated by renal failure (BUN, creatine), renal tissue injury (tubular injury), renal apoptosis, immune cell infiltration in the renal tissue, and inhibition of cytokine secretion in the renal tissue.
The IR PBS control group showed increased serum BUN and creatine levels and increased renal tissue injury, compared with the sham group. However, the PEP 1-administered group showed significantly decreased BUN and creatine levels, and decreased renal tissue injury and renal apoptosis, compared with the control group. Also, the PEP 1-administered group showed inhibited infiltration of inflammatory cells (neutrophils and macrophages) caused by IR in the kidney, and significantly inhibited secretion of inflammatory cytokines (interleukin-6 and monocyte chemotactic protein-1), compared with the PBS control group.
Transplantation of a flap of the rectus abdominis was carried out as follows. An IR injury rat model was obtained by detaching a flap with a size of 5 cm×5 cm from abdominal skin of a white rat (Sprague-Dawley Rat, 180 to 230 g), adding PEP1 or saline to the rat, inducing ischemia through clamping, and restoring blood flow after 7 hours by removing the clamps (refer to
Experimental groups were divided into three groups, which are an administered group (PEP 1), a control group (PBS without PEP 1), and a sham group (group in which no IR injury induced). PEP 1 (10 mg/500 μl) or saline (500 Id) was intramuscularly injected 30 minutes before and 1, 2, 3, 4, 5, and 7 days after the IR induction.
Flap survivability was measured 7 days after the IR induction. The flap survivability was measured through digital image analysis using imageJ program.
According to the measurement 7 days after the IR induction, the flap survivability was 34.69%±16.44% in the saline-treated group, and 58.88%±11.44% in the PEP1-treated group, which was higher than that in the saline-treated group (refer to
A lung transplantation model for examining an effect of PEP1 on preventing IR injury was set as follows.
The experiment was performed using two rats with the same gene, and lung transplantation was carried out by detaching the left lung from a donor rat and placing the donor's lung in the left thoracic cavity from which an original left lung was removed of the recipient rat. To basically prevent rejection, the rats had the same gene. Both the donor rat and recipient rat had weights of 300 to 350 g, and were the Sprague-Dawley species. Following the extraction of a lung from the donor rat, the lung was transplanted to the recipient rat through surgical procedures.
The lung extraction from the donor rat was performed as follows.
{circle around (1)} A mixture of rompun:zoletil (1:2, 1 ml/kg) was intraperitoneally injected into the white rat (donor).
{circle around (2)} Following tracheotomy, a tube with a 16-gauge intravenous catheter was intubated and connected to a ventilator (Harvard Rodent Ventilator Model; Harvard Apparatus CO, Holliston, Mass.) (Vt=10 ml/kg, PEEP=2 cm H2O, respiratory rate=80/min). Mechanical ventilation was carried out with 100% oxygen.
{circle around (3)} Following laprotomy and median sternotomy, 300 IU heparin was injected into the inferior vena cava.
An 18-gauge angio-catheter was inserted into the main pulmonary artery through the right ventricular outflow, and 50 mL normal saline was injected under 20 cm H2O pressure at 10° C. through the main pulmonary artery catheter while the inferior vena cava was divided in the abdominal cavity, and the left atrium was divided. During perfusion, mechanical ventilation was continuously performed to allow uniform lung perfusion.
{circle around (4)} Following the perfusion, trachea was ligated while the lung expanded under the endotracheal intubation, a heart-lung block was extracted, and then peripheral structures such as esophagus were removed on a cold petri-dish. The heart-lung block was weighed, and subjected to cold storage in a perfusion solution, which was the same as the lung perfusion solution. Ischemic duration was set three hours.
The lung to be transplanted was prepared as follows.
{circle around (1)} The extracted lung was placed on a petri-dish containing a cold flush solution, covered with a wet sponge, and then equipped with cuffs. This procedure was performed under hypothermia.
{circle around (2)} After ensuring a sufficient distance for connecting cuffs, the cuffs were attached to a 18 G catheter for the pulmonary artery, a 16 G catheter for the pulmonary vein, and a 16 G catheter for bronchus using 4-0 silk.
Transplant surgery was performed as follows:
{circle around (1)} The recipient rat was sedated by intraperitoneal injection, and after tracheotomy, a tube with a 16-gauge intravenous catheter was intubated, and fixed with 4-0 silk. As for the donor, mechanical ventilation was carried out.
{circle around (2)} Incisions of the pectoralis major and the latissimus dorsi in the right decubitus position, posterolateral thoracotomy was made through the bed of the fourth rib.
{circle around (3)} After cutting the left pulmonary ligament, the left lung was lifted out of the rib cage and held, and then a pulmonary hilum was dissected to expose the pulmonary artery, the pulmonary vein, and the left main stem bronchus.
{circle around (4)} All of the three structures were clamped with microvascular clips (Micro-Serrefine, Fine Science Tools, Foster city, CA).
{circle around (5)} The left lung was removed, and the pulmonary artery, pulmonary vein, and bronchus of the transplanted lung were sutured using a cuff technique.
For the experiment, the lung transplant rats were divided into four groups. To determine a suitable concentration of PEP1, each of low concentration (5 mg) and high concentration (50 mg) of PEP1 were administered into a lung of the donor rat before transplantation, a lung extracted from the donor, and the recipient after transplantation.
To evaluate the function of transplanted lung after transplantation, the following experiments were performed.
When lung injury occurs due to IR injury, hemorrhage occurs, and the alveolar wall is thickened. To measure a degree of the IR injury occurring when the above-mentioned four solutions were used as lung preservation solutions with respect to hemorrhage and a thickness of the alveolar wall, H & E staining was performed as follows.
The intermediate area of the transplanted lung was fixed with formalin, subjected to H & E staining, and then alveolar tissue samples were compared between the groups through optical microscopy.
The analysis showed that hemorrhage and the thickness of the alveolar wall increased in the order of the normal saline group ({circle around (1)} group), the PERFADEX™ (a lightly buffered colloid-based electrolyte preservation solution for rapid cooling, perfusion and storage of organs in connection with transplantation manufacture by XVIVO Perfusion AB) group ({circle around (2)} group), the PERFADEX™ (a lightly buffered colloid-based electrolyte preservation solution for rapid cooling, perfusion and storage of organs in connection with transplantation manufacture by XVIVO Perfusion AB) & PEP1 50 mg group ({circle around (4)} group), and the PERFADEX™ (a lightly buffered colloid-based electrolyte preservation solution for rapid cooling, perfusion and storage of organs in connection with transplantation manufacture by XVIVO Perfusion AB) & PEP1 5 mg group ({circle around (3)} group). Particularly, when the PERFADEX™ (a lightly buffered colloid-based electrolyte preservation solution for rapid cooling, perfusion and storage of organs in connection with transplantation manufacture by XVIVO Perfusion AB) & PEP1 5 mg group ({circle around (3)} group) was used as a lung preservation solution, hemorrhage rarely occurred, and the alveolar wall did not get harder. This shows that, when 5 mg PEP1, rather than 50 mg PEP1, was added to PERFADEX™ (a lightly buffered colloid-based electrolyte preservation solution for rapid cooling, perfusion and storage of organs in connection with transplantation manufacture by XVIVO Perfusion AB), it is more effective in preventing hemorrhage and in maintaining the alveolar wall, which indicate higher IR injury inhibitory effects. (refer to
The lower lobe of the transplanted lung was cut and weighed, dried in an oven at 60° C. for 24 hours, and then weighed again.
The analysis showed that reperfusion edema was increased in the order of the normal saline administered group ({circle around (1)} group), the PERFADEX™ (a lightly buffered colloid-based electrolyte preservation solution for rapid cooling, perfusion and storage of organs in connection with transplantation manufacture by XVIVO Perfusion AB) & PEP1 50 mg administered group ({circle around (4)} group), the PERFADEX™ (a lightly buffered colloid-based electrolyte preservation solution for rapid cooling, perfusion and storage of organs in connection with transplantation manufacture by XVIVO Perfusion AB) administered group ({circle around (2)} group), the PERFADEX™ (a lightly buffered colloid-based electrolyte preservation solution for rapid cooling, perfusion and storage of organs in connection with transplantation manufacture by XVIVO Perfusion AB) & PEP1 5 mg administered group ({circle around (3)} group).
PERFADEX™ (a lightly buffered colloid-based electrolyte preservation solution for rapid cooling, perfusion and storage of organs in connection with transplantation manufacture by XVIVO Perfusion AB) administered group ({circle around (2)} group) and the PERFADEX™ (a lightly buffered colloid-based electrolyte preservation solution for rapid cooling, perfusion and storage of organs in connection with transplantation manufacture by XVIVO Perfusion AB) & PEP1 5 mg administered group ({circle around (3)} group) showed significantly (p<0.05) decreased reperfusion edema, compared with the normal saline administered group ({circle around (1)} group), and the PERFADEX™ (a lightly buffered colloid-based electrolyte preservation solution for rapid cooling, perfusion and storage of organs in connection with transplantation manufacture by XVIVO Perfusion AB) & PEP1 5 mg administered group ({circle around (3)} group) showed the lowest level. (refer to
5 mL normal saline was instillated into the bronchus, and then extracted to be used in an analysis of neutrophil contents.
The analysis showed that rates of inflammatory cells in the BAL were increased in the order of the normal saline administered group ({circle around (1)} group), the PERFADEX™ (a lightly buffered colloid-based electrolyte preservation solution for rapid cooling, perfusion and storage of organs in connection with transplantation manufacture by XVIVO Perfusion AB) administered group ({circle around (2)} group), the PERFADEX™ (a lightly buffered colloid-based electrolyte preservation solution for rapid cooling, perfusion and storage of organs in connection with transplantation manufacture by XVIVO Perfusion AB) & PEP1 50 mg administered group ({circle around (4)} group), and the PERFADEX™ (a lightly buffered colloid-based electrolyte preservation solution for rapid cooling, perfusion and storage of organs in connection with transplantation manufacture by XVIVO Perfusion AB) & PEP1 5 mg administered group ({circle around (3)} group). Arrows indicate inflammatory cells. It was seen that the PERFADEX™ (a lightly buffered colloid-based electrolyte preservation solution for rapid cooling, perfusion and storage of organs in connection with transplantation manufacture by XVIVO Perfusion AB) & PEP1 5 mg administered group ({circle around (3)} group) showed the lowest expression of inflammatory cells (refer to
| Number | Date | Country | Kind |
|---|---|---|---|
| 10-2014-0052536 | Apr 2014 | KR | national |
| PCT/KR2014/004194 | May 2014 | WO | international |
| Filing Document | Filing Date | Country | Kind |
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| PCT/KR2014/004752 | 5/28/2014 | WO | 00 |
| Publishing Document | Publishing Date | Country | Kind |
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| WO2015/167067 | 11/5/2015 | WO | A |
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| Number | Date | Country | |
|---|---|---|---|
| 20170058001 A1 | Mar 2017 | US |
