Patent application title: METHODS FOR REGULATING ENDOGENOUS PRODUCTION OF LACTOFERRIN AND SUB-PEPTIDES THEREOF
Inventors:
IPC8 Class: AC07K1479FI
USPC Class:
1 1
Class name:
Publication date: 2020-01-23
Patent application number: 20200024329
Abstract:
The present disclosure relates to the composition of one or more agents,
therapies, treatments, and methods of use of the agents and/or therapies
and/or treatments for upregulating production of lactoferrin or a
sub-peptide of lactoferrin. Embodiments of the present disclosure can be
used as a therapy or a treatment of adhesions or scarring.Claims:
1. A recombinant virus vector (RVV) comprising a virus with a gene insert
that induces a target cell to increase production of human lactoferrin
protein.
2. The RVV of claim 1, wherein the human lactoferrin protein has an amino acid sequence of SEQ ID No. 1.
3. The RVV of claim 1, wherein the RVV is of a genus that is one of a flavivirus, an influenza, an enterovirus, a rotavirus, a rubellavirus, a rubivirus, a morbillivirus, an orthopoxvirus, a varicellovirus, a dependoparvovirus, an alphabaculovirus, a betabaculovirus, a deltabaculovirus, a gammabaculovirus, a mastadenovirus, a simplexvirus, a varicellovirus, a cytomegalovirus, and combinations thereof.
4. The RVV of claim 1, wherein the gene insert codes for a sub-peptide of the human lactoferrin protein that is between about 5 to about 710 amino acids.
5. The RVV of claim 4, wherein the sub-peptide is a linear sequential sub-peptide.
6. A method of making an agent/target cell complex, the method comprising a step of administering a recombinant virus vector (RVV) to a target cell for forming an agent/target cell complex, wherein the agent/target cell complex causes the target cell to increase a production of the human lactoferrin protein.
7. A method of making an agent/target cell complex, wherein the human lactoferrin protein is a sub-peptide of human lactoferrin protein that is between about 5 to about 710 amino acids.
8. The method of claim 6, wherein the target cell is one or more of an adrenal gland cell; a B cell; a bile duct cell; a chondrocyte; a cochlear cell; a corneal cell; an endocardium cell; an endometrial cell; an endothelial cell; an epithelial cell; an eosinophil; a fibroblast; a hair follicle cell; a hepatocyte; a lymph node cell; a macrophage; a mucosal cell; a myocyte; a neuron; a glomeruli cell; an optic nerve cell; an osteoblast; an ovarian tissue cell; a pancreatic islet beta cell; a pericardium cell; a platelet; a red blood cell (RBC); a retinal cell; a scleral cell; a Schwann cell; a T cell; a testicular tissue cell; a thyroid gland cell; an uveal cell; and combinations thereof
9. A pharmaceutical agent comprising: a. an agent that upregulates production of a human lactoferrin protein; b. a pharmaceutically acceptable carrier; and/or c. an excipient.
10. The pharmaceutical agent of claim 9, wherein the pharmaceutical agent is in a solid form or a liquid form.
11. The pharmaceutical agent of claim 9, wherein the wherein the human lactoferrin protein is a sub-peptide of human lactoferrin protein that is between about 5 to about 710 amino acids.
12. A method of treating a condition, the method comprising a step of administering to a subject a therapeutically effective amount of an agent that upregulates the production of human lactoferrin protein.
13. The method of claim 12, wherein the wherein the human lactoferrin protein is a sub-peptide of human lactoferrin protein that is between about 5 to about 710 amino acids.
14. The method according to claim 12, wherein the condition is the development of one or more adhesions.
15. The method according to claim 12, wherein the condition is scarring.
16. The method according to claim 12, wherein the step of administering occurs by an intravenous route, an intramuscular route, an intraperitoneal route, an intrathecal route, an intravesical route, a topical route, an intranasal route, a transmucosal route, a pulmonary route, and combinations thereof.
17. The method according to claim 12, wherein the therapeutically effective amount is between about 10 to about 1.times.10.sup.16 TCID.sub.50/kg of the patient's body weight.
18. The method according to claim 12, wherein the therapeutically effective amount is between about 10 to about 1.times.10.sup.16 total particles of the agent.
Description:
TECHNICAL FIELD
[0001] The present disclosure generally relates to viral gene vectors engineered to endogenously produce lactoferrin and sub-peptides of lactoferrin. In particular, the present disclosure relates to agents, therapies, and methods of use of the agents and/or therapies for upregulating endogenous production of one or more of lactoferrin and sub-peptides of lactoferrin.
BACKGROUND
[0002] Lactoferrin is one of the transferrin proteins that transfer iron to cells and control the level of free iron in the blood and external secretions. Lactoferrin is present in the milk of humans and other mammals, as well as in the blood plasma and neutrophils, and it is one of the major proteins of virtually all exocrine secretions of mammals, such as pancreatic exocrine secretion, saliva, bile, and tears. The concentration of lactoferrin in milk varies from 7 g/L in the colostrum to 1 g/L in mature milk.
SUMMARY
[0003] Embodiments of the present disclosure relate to inducing endogenous production of lactoferrin or sub-peptides of lactoferrin utilizing gene vectors that contain nucleotide sequences and/or genes for one or more of lactoferrin and/or sub-peptides of lactoferrin.
[0004] Some embodiments of the present disclosure relate to a method of making an agent/target cell complex, the method comprises a step of administering a therapeutically effective amount of the agent to a subject, wherein the agent/target cell complex may increase the subject's production of one or more of lactoferrin and/or sub-peptides of lactoferrin.
[0005] Some embodiments of the present disclosure relate to a method of making an agent/target cell complex, the method comprising a step of administering a sufficient amount of an agent to a target cell whereby the agent/target cell complex is formed, wherein the agent/target cell complex may increase the production of lactoferrin and/or sub-peptides of lactoferrin by said target cell.
[0006] Some embodiments of the present disclosure relate to a pharmaceutical agent that comprises an agent, a pharmaceutically acceptable carrier, and/or an excipient. The agent may upregulate the production of lactoferrin and/or a sub-peptide of lactoferrin.
[0007] Some embodiments of the present disclosure relate to a kit used for treatment of a condition or for delivery of a therapy to a subject. The kit comprises a unit dosage of an agent, a carrier for the unit dosage, and instructions for administering the unit dosage to the subject. The agent may upregulate production of lactoferrin and/or a sub-peptide of lactoferrin. The carrier may be a solid carrier, such as a capsule or tablet, or a liquid. The instructions may describe how the solid carrier may be administered to a subject for an optimal effect. The instructions may also describe how the liquid carrier may be administered to a subject by various routes of administration.
[0008] Some embodiments of the present disclosure relate to a method of treating a condition. The method comprises a step of administering to a subject a therapeutically effective amount of an agent that upregulates a production of lactoferrin and/or a sub-peptide of lactoferrin.
[0009] Without being bound by any particular theory, embodiments of the present disclosure may be useful for treating conditions including adhesions and scarring.
DETAILED DESCRIPTION
Definitions
[0010] Unless defined otherwise, all technical and scientific terms used herein have the meanings that would be commonly understood by one of skill in the art in the context of the present specification. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present disclosure, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and/or materials in connection with which the publications are cited.
[0011] As used herein, the singular forms "a", "an", and "the" include plural references unless the context clearly dictates otherwise. For example, reference to "an agent" includes one or more agents and reference to "a subject" or "the subject" includes one or more subjects.
[0012] As used herein, the terms "about" or "approximately" refer to within about 25%, preferably within about 20%, of a given value or range. It is understood that such a variation is always included in any given value provided herein, whether or not it is specifically referred to.
[0013] As used herein, the term "agent" refers to a substance that, when administered to a patient, causes one or more chemical reactions and/or one or more physical reactions and/or or one or more physiologic reactions in the patient.
[0014] As used herein, the term "cell" refers to a single cell as well as a plurality of cells or a population of the same cell type or different cell types. Administering an agent to a cell includes in vivo, in vitro and ex vivo administrations or combinations thereof.
[0015] As used herein, the term "complex" refers to an association, either direct or indirect, between one or more particles of an agent and one or more target cells. This association results in a change in the metabolism of the target cell. As used herein, the phrase "change in metabolism" refers to an increase or a decrease in the one or more target cells' production of deoxyribonucleic acid (DNA), ribonucleic acid (RNA), one or more proteins, or any post-translational modifications of one or more proteins.
[0016] As used herein, the term "excipient" refers to any substance, not itself an agent, which may be used as a component within a pharmaceutical composition or a medicament for administration of a therapeutically effective amount of the agent to a subject. Additionally or alternatively, an excipient may alone, or in combination with further chemical components, improve the handling and/or storage properties and/or to permit or facilitate formation of a dose unit of the agent. Excipients include, but are not limited to, one or more of: a binder, a disintegrant, a diluent, a buffer, a solvent, a thickening agent, a gelling agent, a penetration enhancer, a solubilizing agent, a wetting agent, an antioxidant, a preservative, a surface active agent, a lubricant, an emollient, a substance added to improve the appearance or texture of the composition, and a substance used to form the pharmaceutical compositions or medicaments. Any such excipients can be used in any dosage forms according to the present disclosure. The foregoing classes of excipients are not meant to be exhaustive but are provided merely as illustrative of what a person of skill in the art would know; a person of skill in the art would also recognize that additional types and combinations of excipients may be used to achieve delivery of a therapeutically effective amount of the agent to a subject through one or more routes of administration.
[0017] As used herein, the term "medicament" refers to a medicine and/or pharmaceutical composition that comprises the agent and that can promote recovery from a disease, disorder or symptom thereof and/or that can prevent a disease, disorder or symptom thereof and/or that can inhibit the progression of a disease, disorder, or symptom thereof.
[0018] As used herein, the term "patient" refers to a subject that is afflicted with a disease or disorder. The term "patient" includes human and veterinary subjects.
[0019] As used herein, the term "pharmaceutical composition" means any composition for administration of the agent to a subject in need of therapy or treatment of a disease, disorder or symptom thereof. Pharmaceutical compositions may include additives such as pharmaceutically acceptable carriers, pharmaceutically accepted salts, excipients and the like. Pharmaceutical compositions may also additionally include one or more further active ingredients such as antimicrobial agents, anti-inflammatory agents, anaesthetics, analgesics, and the like.
[0020] As used herein, the term "pharmaceutically acceptable carrier" refers to an essentially chemically inert and nontoxic component within a pharmaceutical composition or medicament that does not inhibit the effectiveness and/or safety of the agent. Some examples of pharmaceutically acceptable carriers and their formulations are described in Remington (1995, The Science and Practice of Pharmacy (19th ed.) ed. A. R. Gennaro, Mack Publishing Company, Easton, Pa.), the disclosure of which is incorporated herein by reference. Typically, an appropriate amount of a pharmaceutically acceptable carrier is used in the formulation to render the formulation isotonic. Examples of suitable pharmaceutically acceptable carriers include, but are not limited to: saline solutions, glycerol solutions, ethanol, N-(1(2, 3 -dioleyloxy)propyl)-N,N,N-trimethylammonium chloride (DOTMA), diolesylphosphotidylethanolamine (DOPE), and liposomes of various constituents. Such pharmaceutical compositions contain a therapeutically effective amount of the agent, together with a suitable amount of one or more pharmaceutically acceptable carriers and/or excipients so as to provide a form suitable for proper administration to the subject. The formulation should suit the route of administration. For example, oral administration may require that the formulation incorporate enteric coatings to protect the agent from degrading within portions of the subject's gastrointestinal tract. In another example, injectable routes of administration may be administered in a liposomal formulation to facilitate transport throughout a subject's vascular system and to facilitate delivery across cell membranes of targeted intracellular sites.
[0021] As used herein, the phrases "prevention of" and "preventing" refer to avoiding an onset or progression of a disease, disorder, or a symptom thereof.
[0022] As used herein, the terms "production", "producing" and "produce" refer to the synthesis and/or replication of DNA, the transcription of one or more sequences of RNA, the translation of one or more amino acid sequences, the post-translational modifications of amino acid sequences, and/or the production or functionality of one or more regulatory molecules that can influence the production or functionality of an effector molecule.
[0023] As used herein, the terms "promote", "promotion", and "promoting" refer to an increase in an activity, response, condition, disease, or other biological parameter. This can include but is not limited to the initiation of the activity, response, condition, or disease. This may also include, for example, a 10% increase in the activity, response, condition, or disease as compared to the native or control level. Thus, the increase in an activity, response, condition, disease, or other biological parameter can be 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 100%, or more, including any amount of increase in between the specifically recited percentages, as compared to native or control levels.
[0024] As used herein, the term "prophylactic administration" refers to the administration of any composition to a subject, in the absence of any symptom or indication of a disease or disorder, to prevent the occurrence of and/or the progression of the disease or disorder within the subject.
[0025] As used herein, the term "subject" refers to any therapeutic target that receives the agent. The subject can be a vertebrate, for example, a mammal including a human. The term "subject" does not denote a particular age or sex. The term "subject" also refers to one or more cells of an organism; an in vitro culture of one or more tissue types, an in vitro culture of one or more cell types; ex vivo preparations; and a sample of biological materials such as tissue and/or biological fluids.
[0026] As used herein, the term "target cell" refers to one or more cells that are deleteriously affected, either directly or indirectly, by a dysregulated immune system.
[0027] As used herein, the terms "treat", "treatment" and "treating" refer to obtaining a desired pharmacologic and/or physiologic effect. The effect may be prophylactic in terms of completely or partially preventing an occurrence of a disease, disorder or symptom thereof and/or may be therapeutic in providing a partial or complete amelioration or inhibition of a disease, disorder, or symptom thereof. Additionally, the term "treatment" refers to any treatment of a disease, disorder, or symptom thereof in a subject and includes: (a) preventing the disease from occurring in a subject which may be predisposed to the disease but has not yet been diagnosed as having it; (b) inhibiting the disease, i.e., arresting its development; and (c) ameliorating the disease.
[0028] As used herein, the term "therapeutically effective amount" refers to the amount of the agent used that is of sufficient quantity to ameliorate, treat and/or inhibit one or more of a disease, disorder or a symptom thereof. The "therapeutically effective amount" will vary depending on the agent used, the route of administration of the agent, and the severity of the disease, disorder or symptom thereof. The subject's age, weight and genetic make-up may also influence the amount of the agent that will be a therapeutically effective amount.
[0029] As used herein, the terms "unit dosage form" and "unit dose" refer to a physically discrete unit that is suitable as a unitary dose for patients. Each unit contains a predetermined quantity of the agent and optionally, one or more suitable pharmaceutically acceptable carriers, one or more excipients, one or more additional active-ingredients, or combinations thereof. The amount of agent within each unit is a therapeutically effective amount.
[0030] In one embodiment of the present disclosure, the pharmaceutical compositions disclosed herein comprise an agent as described above in a total amount by weight of the composition of about 0.1% to about 2%. For example, the amount of the agent by weight of the pharmaceutical composition may be about 0.1%, about 0.2%, about 0.3%, about 0.4%, about 0.5%, about 0.6%, about 0.7%, about 0.8%, about 0.9%, about 1%, about 1.1%, about 1.2%, about 1.3%, about 1.4%, about 1.5%, about 1.6%, about 1.7%, about 1.8%, about 1.9%, or about 2%.
[0031] Where a range of values is provided herein, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the disclosure. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also, encompassed within the disclosure, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the disclosure.
[0032] The present disclosure relates to one or more agents, therapies, treatments and methods of use of the agents and/or therapies and/or treatments for upregulating production of a lactoferrin protein and/or a sub-peptide of lactoferrin. For the purposes of the present disclosure, the term "lactoferrin protein" includes sub-peptides thereof. Some embodiments of the present disclosure relate to methods for making a complex between at least one particle of an agent and at least one target cell of a subject for upregulating that subject's production of lactoferrin and/or a sub-peptide of lactoferrin.
[0033] In some embodiments of the present disclosure, the agent can be administered to the subject by: an intravenous route, an intramuscular route, an intraperitoneal route, an intrathecal route, an intravesical route, a topical route, an intranasal route, a transmucosal route, a pulmonary route, an oral route or combinations thereof
[0034] In some embodiments of the present disclosure, the agent can be administered to the subject by pipetting a dose of the agent into an in vitro cell culture, perfusing or immersing an ex vivo cell or tissue preparation with a solution that comprises the agent, mixing a biological fluid sample with a solution or substrate that comprises the agent, or combinations thereof.
[0035] Some embodiments of the present disclosure relate to an agent that can be administered to a subject with a condition that is associated, either directly or indirectly with the subject forming an adhesion and/or scars. When a therapeutically effective amount of the agent is administered to the subject, the subject may change production and/or functionality of one or more immune-system molecules. For example, the subject may increase production of lactoferrin and/or a sub-peptide of lactoferrin by changing the production of one or more sequences of DNA, one or more sequences of RNA and/or one or more proteins and/or one or more regulatory molecules that regulate the subject's levels of lactoferrin and/or a sub-peptide of lactoferrin.
[0036] In some embodiments of the present disclosure, the subject may respond to receiving the therapeutic amount of the agent by changing production of lactoferrin and/or a sub-peptide of lactoferrin by changing production and/or functionality of one or more DNA sequences, one or more RNA sequences, and/or one or more proteins that regulate the levels and/or functionality of the one or more intermediary molecules. The one or more intermediary molecules regulate the subject's levels of lactoferrin and/or a sub-peptide of lactoferrin.
[0037] In some embodiments of the present disclosure, the agent can be: a vector used for gene therapy; one or more selected nucleotides, a sequence of nucleotides, one or more nucleosides, a sequence of nucleosides, a RNA complex, a DNA complex or combinations thereof.
[0038] In some embodiments of the present disclosure, the agent is a vector that comprises a gene insert, for example a recombinant virus vector (RVV), used for gene therapy. The gene therapy is useful for increasing the production of lactoferrin and/or a sub-peptide of lactoferrin.
[0039] In some embodiments of the present disclosure, the agent is a virus that can be within one or more of the following genus: flavivirus, influenza, enterovirus, rotavirus, rubellavirus, rubivirus, morbillivirus, orthopoxvirus, varicellovirus, dependoparvovirus, alphabaculovirus, betabaculovirus, deltabaculovirus, gammabaculovirus, mastadenovirus, simplexvirus, varicellovirus, cytomegalovirus, or combinations thereof.
[0040] Some embodiments of the present disclosure also relate to administering a therapeutically effective amount of the agent. The therapeutically effective amount of the agent will not substantially increase or advance any deleterious conditions within the subject. For example, the therapeutically effective amount will not cause cytokinesis, hypercytokinemia, or any other uncontrolled, or partially controlled, upregulation of the subject's immune system. In some embodiments of the present disclosure, the therapeutically effective amount of the agent that is administered to a patient is between about 10 and about 1.times.10.sup.16 TCID.sub.50/kg (50% tissue culture infective dose per kilogram of the patient's body weight). In some embodiments of the present disclosure the therapeutically effective amount of the agent that is administered to the patient is about 1.times.10.sup.13 TCID.sub.50/kg. In some embodiments of the present disclosure, the therapeutically effective amount of the agent that is administered to a patient is measured in TPC/kg (total particle count of the agent per kilogram of the patient's body weight). In some embodiments the therapeutically effective amount of the agent is between about 10 and about 1.times.10.sup.16 TCP/kg.
[0041] Some embodiments of the present disclosure relate to a method for making a complex within a subject. The method comprises a step of administering a therapeutically effective amount of the agent to the subject. The complex comprises at least one particle of the agent, and one or more target cells. When the complex is formed, it affects a change in metabolism of the one or more target cells that may result in the subject upregulating the production of lactoferrin and/or a sub-peptide of lactoferrin. Examples of a target cell include, but are not limited to: an adrenal gland cell, a B cell, a bile duct cell, a chondrocyte, a cochlear cell, a corneal cell, an endocardium cell, an endometrial cell, an endothelial cell, an epithelial cell, an eosinophil, a fibroblast, a hair follicle cell, a hepatocyte, a lymph node cell, a neutrophil, a macrophage, a mucosal cell, a myocyte, a neuron, a glomeruli cell, an optic nerve cell, an osteoblast, an ovarian tissue cell, a pancreatic islet beta cell, a pericardium cell, a platelet, a red blood cell (RBC), a retinal cell, a scleral cell, a Schwann cell, a T cell, a testicular tissue cell, a thyroid gland cell, an uveal cell, or combinations thereof.
[0042] Some embodiments of the present disclosure relate to a therapy that can be administered to a subject with the condition. The therapy comprises a step of administering to the subject a therapeutically effective amount of an agent that will upregulate production of lactoferrin or a sub-peptide of lactoferrin. When the therapy is administered to a patient, the therapy will promote the in vivo production of lactoferrin and/or a sub-peptide of lactoferrin.
[0043] Some embodiments of the present disclosure relate to a method of treating a condition where the method comprises a step of administering to the subject a therapeutically effective amount of an agent that will upregulate production of lactoferrin and/or a sub-peptide of lactoferrin.
EXAMPLE
[0044] In one example, the agent is a gene vector that includes a gene insert for the gene responsible for producing lactoferrin protein in humans. In this example, the gene insert produces a biological compound with the following amino-acid sequence (SEQ ID No. 1):
TABLE-US-00001 MKLVFLVLLFLGALGLCLAGRRRRSVQWCAVSQPEATKCFQWQRNMRR VRGPPVSCIKRDSPIQCIQAIAENRADAVTLDGGFIYEAGLAPYKLRP VAAEVYGTERQPRTHYYAVAVVKKGGSFQLNELQGLKSCHTGLRRNAG WNVPIGTLRPFLNWTGPPEPIEAAVARFFSASCVPGADKGQFPNLCRL CAGTGENKCAFSSQEPYFSYSGAFKCLRDGAGDVAFIRESTVFEDLSD EAERDEYELLCPDNTRKPVDKFKDCHLARVPSHAVVARSVNGKEDAIW NLLRQAQEKFGKDKSPKFQLFGSPSGQKDLLFKDSAIGFSRVPPRIDS GLYLGSGYFTAIQNLRKSEEEVAARRARVVWCAVGEQELRKCNQWSGL SEGSVTCSSASTTEDCIALVLKGEADAMSLDGGYVYTAGKCGLVPVLA ENYKSQQSSDPDPNCVDRPVEGYLAVAVVRRSDTSLTWNSVKGKKSCH TAVDRTAGWNIPMGLLFNQTGSCKFDEYFSQSCAPGSDPRSNLCALCI GDEQGENKCVPNSNERYYGYTGAFRCLAEDAGDVAFVKGVTVLQNTDG NNNEAWAKDLKLADFALLCLDGKRKPVTEARSCHLAMAPNHAVVSRMD KVERLKQVLLHQQAKFGRNGSDCPDKFCLFQSETKNLLFNDNTECLAR LHGKTTYEKYLGPQYVAGITNLKKCSTSPLLEACEFLRK
Sequence CWU
1
1
11711PRTHomo sapiens 1Met Lys Leu Val Phe Leu Val Leu Leu Phe Leu Gly Ala
Leu Gly Leu1 5 10 15Cys
Leu Ala Gly Arg Arg Arg Arg Ser Val Gln Trp Cys Ala Val Ser 20
25 30Gln Pro Glu Ala Thr Lys Cys Phe
Gln Trp Gln Arg Asn Met Arg Arg 35 40
45Val Arg Gly Pro Pro Val Ser Cys Ile Lys Arg Asp Ser Pro Ile Gln
50 55 60Cys Ile Gln Ala Ile Ala Glu Asn
Arg Ala Asp Ala Val Thr Leu Asp65 70 75
80Gly Gly Phe Ile Tyr Glu Ala Gly Leu Ala Pro Tyr Lys
Leu Arg Pro 85 90 95Val
Ala Ala Glu Val Tyr Gly Thr Glu Arg Gln Pro Arg Thr His Tyr
100 105 110Tyr Ala Val Ala Val Val Lys
Lys Gly Gly Ser Phe Gln Leu Asn Glu 115 120
125Leu Gln Gly Leu Lys Ser Cys His Thr Gly Leu Arg Arg Asn Ala
Gly 130 135 140Trp Asn Val Pro Ile Gly
Thr Leu Arg Pro Phe Leu Asn Trp Thr Gly145 150
155 160Pro Pro Glu Pro Ile Glu Ala Ala Val Ala Arg
Phe Phe Ser Ala Ser 165 170
175Cys Val Pro Gly Ala Asp Lys Gly Gln Phe Pro Asn Leu Cys Arg Leu
180 185 190Cys Ala Gly Thr Gly Glu
Asn Lys Cys Ala Phe Ser Ser Gln Glu Pro 195 200
205Tyr Phe Ser Tyr Ser Gly Ala Phe Lys Cys Leu Arg Asp Gly
Ala Gly 210 215 220Asp Val Ala Phe Ile
Arg Glu Ser Thr Val Phe Glu Asp Leu Ser Asp225 230
235 240Glu Ala Glu Arg Asp Glu Tyr Glu Leu Leu
Cys Pro Asp Asn Thr Arg 245 250
255Lys Pro Val Asp Lys Phe Lys Asp Cys His Leu Ala Arg Val Pro Ser
260 265 270His Ala Val Val Ala
Arg Ser Val Asn Gly Lys Glu Asp Ala Ile Trp 275
280 285Asn Leu Leu Arg Gln Ala Gln Glu Lys Phe Gly Lys
Asp Lys Ser Pro 290 295 300Lys Phe Gln
Leu Phe Gly Ser Pro Ser Gly Gln Lys Asp Leu Leu Phe305
310 315 320Lys Asp Ser Ala Ile Gly Phe
Ser Arg Val Pro Pro Arg Ile Asp Ser 325
330 335Gly Leu Tyr Leu Gly Ser Gly Tyr Phe Thr Ala Ile
Gln Asn Leu Arg 340 345 350Lys
Ser Glu Glu Glu Val Ala Ala Arg Arg Ala Arg Val Val Trp Cys 355
360 365Ala Val Gly Glu Gln Glu Leu Arg Lys
Cys Asn Gln Trp Ser Gly Leu 370 375
380Ser Glu Gly Ser Val Thr Cys Ser Ser Ala Ser Thr Thr Glu Asp Cys385
390 395 400Ile Ala Leu Val
Leu Lys Gly Glu Ala Asp Ala Met Ser Leu Asp Gly 405
410 415Gly Tyr Val Tyr Thr Ala Gly Lys Cys Gly
Leu Val Pro Val Leu Ala 420 425
430Glu Asn Tyr Lys Ser Gln Gln Ser Ser Asp Pro Asp Pro Asn Cys Val
435 440 445Asp Arg Pro Val Glu Gly Tyr
Leu Ala Val Ala Val Val Arg Arg Ser 450 455
460Asp Thr Ser Leu Thr Trp Asn Ser Val Lys Gly Lys Lys Ser Cys
His465 470 475 480Thr Ala
Val Asp Arg Thr Ala Gly Trp Asn Ile Pro Met Gly Leu Leu
485 490 495Phe Asn Gln Thr Gly Ser Cys
Lys Phe Asp Glu Tyr Phe Ser Gln Ser 500 505
510Cys Ala Pro Gly Ser Asp Pro Arg Ser Asn Leu Cys Ala Leu
Cys Ile 515 520 525Gly Asp Glu Gln
Gly Glu Asn Lys Cys Val Pro Asn Ser Asn Glu Arg 530
535 540Tyr Tyr Gly Tyr Thr Gly Ala Phe Arg Cys Leu Ala
Glu Asp Ala Gly545 550 555
560Asp Val Ala Phe Val Lys Gly Val Thr Val Leu Gln Asn Thr Asp Gly
565 570 575Asn Asn Asn Glu Ala
Trp Ala Lys Asp Leu Lys Leu Ala Asp Phe Ala 580
585 590Leu Leu Cys Leu Asp Gly Lys Arg Lys Pro Val Thr
Glu Ala Arg Ser 595 600 605Cys His
Leu Ala Met Ala Pro Asn His Ala Val Val Ser Arg Met Asp 610
615 620Lys Val Glu Arg Leu Lys Gln Val Leu Leu His
Gln Gln Ala Lys Phe625 630 635
640Gly Arg Asn Gly Ser Asp Cys Pro Asp Lys Phe Cys Leu Phe Gln Ser
645 650 655Glu Thr Lys Asn
Leu Leu Phe Asn Asp Asn Thr Glu Cys Leu Ala Arg 660
665 670Leu His Gly Lys Thr Thr Tyr Glu Lys Tyr Leu
Gly Pro Gln Tyr Val 675 680 685Ala
Gly Ile Thr Asn Leu Lys Lys Cys Ser Thr Ser Pro Leu Leu Glu 690
695 700Ala Cys Glu Phe Leu Arg Lys705
710
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