WO2024258622A1 - Fractions de plasma sanguin en tant que traitement de troubles cognitifs induits par la chimiothérapie - Google Patents

Fractions de plasma sanguin en tant que traitement de troubles cognitifs induits par la chimiothérapie Download PDF

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WO2024258622A1
WO2024258622A1 PCT/US2024/031597 US2024031597W WO2024258622A1 WO 2024258622 A1 WO2024258622 A1 WO 2024258622A1 US 2024031597 W US2024031597 W US 2024031597W WO 2024258622 A1 WO2024258622 A1 WO 2024258622A1
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plasma
cisplatin
fraction
treatment
blood
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WO2024258622A9 (fr
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Ian GALLAGER
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Alkahest Inc
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Alkahest Inc
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/16—Blood plasma; Blood serum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/66—Microorganisms or materials therefrom
    • A61K35/76—Viruses; Subviral particles; Bacteriophages
    • 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
    • A61K38/38—Albumins
    • A61K38/385—Serum albumin

Definitions

  • This invention pertains to the prevention and treatment of chemotherapy induced cognitive disorders, such as chemotherapy induced cognitive impairment (CICI).
  • CICI chemotherapy induced cognitive impairment
  • the invention relates to the use of blood products, such as blood plasma fractions, to treat and/or prevent cognitive disorders, e.g., impairment associated with chemotherapy, such as CICI.
  • Cisplatin (CisPt) and other platinum (Pt)-based antineoplastic drugs are highly effective and widely used in the treatment of solid tumors in both children and adult patients.
  • the antineoplastic mechanism of CisPt involves formation of intrastrand cross-links that disrupt the DNA helical structure necessary for transcription. This initiates apoptotic cell death through DNA damage-recognition pathways.
  • the present disclosure is based on the production and use of blood products for treating and/or preventing chemotherapy induced cognitive disorders, such as CICI.
  • the compositions described in this disclosure relate to a solution for the failures and shortcomings of current therapies.
  • blood plasma fractions disclosed herein exhibit efficacy in the treatment and/or prevention of chemotherapy induced cognitive disorders, such as CICI.
  • the disclosure relates to proteins identified in blood plasma fractions that either may exhibit efficacy as treatments or preventative agents for chemotherapy induced cognitive disorders, such as CICI.
  • the disclosure also describes that differences in protein content between different blood plasma fractions (e.g., fractions, effluents, “Plasma Fractions,” Plasma Protein Fraction, Human Albumin Solution) can be responsible for preventing and/or improving certain cognitive impairments associated with chemotherapy.
  • fractions, effluents, “Plasma Fractions,” Plasma Protein Fraction, Human Albumin Solution can be responsible for preventing and/or improving certain cognitive impairments associated with chemotherapy.
  • Certain aspects of the disclosure provide, methods of treating or preventing chemotherapy induced cognitive disorder, e.g., CICI.
  • Certain aspects of the methods disclosed herein include administering a blood plasma fraction to an individual suffering from or at risk of developing a chemotherapy induced cognitive disorder, e.g., CICI. Additional aspects of the methods include administering a blood plasma fraction derived from a pool of donors of a specific age range to an individual suffering from or at risk of developing a chemotherapy induced cognitive disorder, such as CICI.
  • reagents, devices, and kits thereof that find use in practicing the subject methods.
  • the blood plasma fraction may be, for example, one of several blood plasma fractions obtained from a blood fractionation process, such as the Cohn fractionation process described below.
  • the blood plasma fraction may be of the type, herein referred to as “Plasma Fraction,” which is a solution comprised of one or more of human albumin, alpha and beta globulins, gamma globulin, and other proteins, either individually or as complexes.
  • the blood plasma fraction may be a type of blood plasma fraction known to those having skill in the art as a “Plasma Protein Fraction” (PPF).
  • PPF PPF
  • the blood plasma fraction may be a “Human Albumin Solution” (HAS) fraction.
  • HAS Human Albumin Solution
  • the blood plasma fraction may one in which substantially all of the clotting factors are removed to retain the efficacy of the fraction with reduced risk of thromboses.
  • Embodiments of the invention may also include administering, for example, a fraction derived from a young donor or pools of young donors.
  • Another embodiment of the invention may include the monitoring of cognitive improvement in a subject treated with a blood plasma fraction.
  • FIG. 1 Certain examples of symptoms of a CICI.
  • FIGS. 2A-2C Certain molecular effects involved in the development of CICI. Effects of chemotherapy on proliferation (A), neurogenesis (B), and BBB permeability (C) are shown.
  • A effects of chemotherapy on proliferation
  • B neurogenesis
  • C BBB permeability
  • bars from left to right vehicle, 1 mg/kg cisplatin, 1 mg/kg cisplatin + 100 mg/kg metformin, 2.3 mg/kg cisplatin, 2.3 mg/kg cisplatin + 100 mg/kg metformin.
  • FIGS. 3A-3B Experimental design and core concept.
  • B Comparison of conventional line scan approach and segmentation detection.
  • FIGS. 5A-5D show total extravascular AQP4 signal by cisplatin treatment.
  • the top panel shows the data for 24 weeks
  • the middle panel shows the data for 2 weeks
  • the bottom panel shows the data for 6 weeks.
  • the dotted line graph represents vehicle treated and solid line represents 2.3 mg/kg cisplatin treated mice.
  • the lighter bars show vehicle treated and darker bars show 2.3 mg/kg cisplatin treated mice.
  • A. The area in pixels contained in each shell starting at 5 pm to 30 pm from nearest vascular (lectin+) segment at 24 hours, 2 weeks, and 6 weeks post cisplatin treatment.
  • B The area under the curve (AUC) generated from line graphs in A.
  • FIGS. 6A-6B Cisplatin-induced BBB leakage of sodium fluorescein correlates with extravascular AQP4 signal.
  • the top panel shows the data for 24 weeks and the bottom panel shows the data for 6 weeks.
  • A shows sodium fluorescein (NaF) signal (RFU) in cortex homogenate from 24 hour and 6 week samples as a measurement of extravasation. The lighter bars show vehicle treated and darker bars show 2.3 mg/kg cisplatin treated mice.
  • B Sodium fluorescein strongly correlated with 20 pm shell AQP4 signal at 24 hours but not 6 weeks. The circles show the data for vehicle treated and triangles show the data for 2.3 mg/kg cisplatin treated mice.
  • FIGS. 7A-7B show that the segmentation method detects AQP4 mislocalization up to 2 weeks post-cisplatin treatment.
  • the top panel shows the data from 24 weeks
  • the middle panel shows the data from 2 weeks
  • the bottom panel shows the data from 6 weeks.
  • A. AQP4-AF647 fluorescence (RFU) measured in each 5 pm shell from nearest vascular segment normalized to total area (pixels) contained in the shell (as measured in FIG. 5A).
  • the circles show the data for vehicle treated and triangles show the data for 2.3 mg/kg cisplatin treated mice.
  • FIGS. 9A-9D Cisplatin impact on oligodendrocyte is stage-specific.
  • a and B Representative 200 pm by 200 pm CAI images demonstrating oligodendrocytes (OL) (white), oligodendrocyte precursor cells (OPCs) (red), mature OLs (green), and DAPI (blue). Yellow arrow indicates a colocalizing cell.
  • C Effects of cisplatin treatment on OPC population measured by OLIG2+ GPR17+ colocalized cell counts in the hippocampus at 3, 14, or 42 days following the last cisplatin treatment. Cisplatin treated group was normalized to vehicle treated group and analyzed by Mann-Whitney tests, p ⁇ 0.05.
  • D D.
  • Cisplatin treated group was normalized to vehicle treated group and analyzed by Mann- Whitney tests.
  • FIGS. 10A-10B Metformin attenuates cisplatin impact on OPC.
  • A Fold change from vehicle treatment group of count per mm 2 quantification of OLIG2+, GPR17+, or GSTTI-I- cells at 3 days post cisplatin and Metformin treatment. Cisplatin treated group was normalized to vehicle treated group and analyzed by Kruskal-Wallis tests with Dunn’s multiple comparisons.
  • B Fold change from vehicle treatment group of count per mm2 quantification of OLIG2+, GPR17+, or GSTTH- cells at 14 days post cisplatin and Metformin treatment. Cisplatin treated group was normalized to vehicle treated group and analyzed by Kruskal-Wallis tests with Dunn’s multiple comparisons.
  • FIG. 11 SOD plasma level is increased with cisplatin treatment. Data was analyzed by Kruskal-Wallis tests with Dunn’s multiple comparisons. *** p ⁇ 0.001, **p ⁇ 0.01, *p ⁇ 0.05.
  • FIGS. 12A-12B Relative pattern changes and association of oligodendrocyte population and oxidative stress.
  • A General changes in oligodendrocyte lineage cell population pattern with cisplatin treatment.
  • B Relationship between oligodendrocyte population and oxidative stress level with and without prophylactic Metformin treatment. Left panel illustrates general changes in oligodendrocyte lineage cell population pattern with cisplatin treatment. Right panel shows relationship between oligodendrocyte population and oxidative stress level with and without prophylactic metformin treatment.
  • FIGS. 13A-13F PPF shows modest improvement in spatial cognition in cisplatin treated mice as estimated in a Y-maze assay.
  • D 2-trial Y-maze layout, training and testing time, and ITI (intertrial interval) obtained from Sithisarn et al. (2013), Hindawi Publishing Corporation, Evidence-Based Complementary and Alternative Medicine Volume 2013, Article ID 701956, 9 pages).
  • FIGS. 14A-14G PPF (identified as PF in this Figure) moderately attenuates neurogenesis and reductions in proliferation in cisplatin treated mice.
  • the present disclosure relates to the identification and discovery of methods and compositions for the treatment and/or prevention of chemotherapy induced cognitive disorders, e.g., CICI.
  • chemotherapy induced cognitive disorders e.g., CICI.
  • Described herein in some embodiments are methods and compositions for the treatment of subjects suffering from such disorders.
  • the methods and compositions described herein are useful in: preventing chemotherapy induced cognitive disorders, e.g., CICI; ameliorating the symptoms of chemotherapy induced cognitive disorders, e.g., CICI; slowing progression of chemotherapy induced cognitive disorders, e.g., CICI; and/or reversing the progression of chemotherapy induced cognitive disorders, e.g., CICI.
  • FIG. 1 Certain nervous system related symptoms of chemotherapy induced cognitive disorders are provided in FIG. 1. Moreover, certain molecular effects of chemotherapy induced neurological changes are described in FIGS. 2A-2C.
  • Certain embodiments of the disclosure include using in the methods disclosed herein certain blood plasma fractions, such as one or more fractions or effluents obtained from blood fractionation processes, e.g., the Cohn fractionation process described below.
  • An embodiment of the invention includes using a Plasma Fraction (a solution comprised of normal human albumin, alpha and beta globulins, gamma globulin, and other proteins either individually or as complexes, hereinafter referred to as “Plasma Fraction”).
  • Plasma Fraction a solution comprised of normal human albumin, alpha and beta globulins, gamma globulin, and other proteins either individually or as complexes, hereinafter referred to as “Plasma Fraction”).
  • Another embodiment of the invention includes using in the methods disclosed herein Plasma Protein Fraction (PPF).
  • a further embodiment of the invention includes using in the methods disclosed herein Human Albumin Solution (HAS) fraction.
  • Plasma Fraction a solution comprised of normal human albumin, al
  • Yet another embodiment includes using in the methods disclosed herein effluents from blood fractionation processes such as Effluent I or Effluent II/III.
  • An additional embodiment includes using in the methods disclosed herein a blood plasma fraction from which substantially all the clotting factors have been removed to retain efficacy while reducing the risk of thromboses.
  • the terms “host,” “subject,” “individual,” and “patient” are used interchangeably and refer to any mammal in need of such treatment according to the disclosed methods.
  • Such mammals include, e.g., humans, ovines, bovines, equines, porcines, canines, felines, non-human primate, mice, and rats.
  • the subject is a non-human mammal.
  • the subject is a farm animal.
  • the subject is a pet.
  • the subject is mammalian. In certain instances, the subject is human.
  • subjects can include domestic pets (e.g., dogs and cats), livestock (e.g., cows, pigs, goats, horses, and the like), rodents (e.g., mice, guinea pigs, and rats, e.g., as in animal models of disease), as well as non-human primates (e.g., chimpanzees, and monkeys).
  • livestock e.g., cows, pigs, goats, horses, and the like
  • rodents e.g., mice, guinea pigs, and rats, e.g., as in animal models of disease
  • non-human primates e.g., chimpanzees, and monkeys
  • subjects of the invention include but are not limited to mammals, e.g., humans and other primates, such as chimpanzees and other apes and monkey species; and the like, where in certain embodiments the subject are humans.
  • the term subject is also meant to include a person or organism of any age, weight or other physical characteristic, where the subjects may be an adult, a child, an infant or a newborn.
  • the term “young” or “young individual” as it relates humans refers to an individual human that is of chronological age of 40 years old or younger, c.g., 35 years old or younger, including 30 years old or younger, e.g., 25 years old or younger or 22 years old or younger.
  • the individual human that serves as the source of the young plasma-comprising blood product is one that is 10 years old or younger, e.g., 5 years old or younger, including 1-year-old or younger.
  • the subject is a newborn human and the source of the plasma product is the umbilical cord, where the plasma product is harvested from the umbilical cord of the newborn human.
  • “young” and “young individual” may refer to a human that is between the ages of 0 and 40, e.g., 0, 1, 5, 10, 15, 20, 25, 30, 35, or 40 years old.
  • “young” and “young individual” may refer to a biological (as opposed to chronological) age such as an individual who has not exhibited the levels of inflammatory cytokines in the plasma exhibited in comparatively older individuals.
  • these “young” and “young individual” may refer to a biological (as opposed to chronological) age such as an individual who exhibits greater levels of anti-inflammatory cytokines in the plasma compared to levels in comparatively older individuals.
  • the inflammatory cytokine is Eotaxin
  • the fold difference between a young subject or young individual and older individuals is at least 20%.
  • the fold difference between older and younger individuals in other inflammatory cytokines may be used to refer to a biological age.
  • the individual is healthy, e.g., the individual has no hematological malignancy or autoimmune disease at the time of harvest.
  • young or “young individual” as it may relate to a non-human animal species refers to an animal considered “young” in the corresponding animal species depending on the life- span/life-cycle of the individuals of the animal species.
  • treatment refers to any of (i) the prevention of the disease or disorder, or (ii) the reduction or elimination of symptoms of the disease or disorder. Treatment may be effected prophylactically (prior to the onset of disease) or therapeutically (following the onset of the disease). The effect may be prophylactic in terms of completely or partially preventing a disease or symptom thereof and/or may be therapeutic in terms of a partial or complete cure for a disease and/or adverse effect attributable to the disease.
  • treatment covers any treatment of a chemotherapy induced cognitive disorder, e.g., CICI, in a mammal, 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.c., arresting its development; or (c) relieving the disease, i.e., causing regression of the disease.
  • Treatment may result in a variety of different physical manifestations, e.g., modulation in gene expression, rejuvenation of tissue or organs, etc.
  • the therapeutic agent may be administered before, during or after the onset of disease.
  • the treatment of ongoing disease where the treatment stabilizes or reduces the undesirable clinical symptoms of the patient, is of particular interest. Such treatment may be performed prior to complete loss of function in the affected tissues.
  • the subject therapy may be administered during the symptomatic stage of the disease, and in some cases after the symptomatic stage of the disease.
  • the disorder that is treated is chemotherapy induced cognitive disorder, e.g., CICI.
  • cognitive ability or “cognition” it is meant the mental processes that include attention and concentration, learning complex tasks and concepts, memory (acquiring, retaining, and retrieving new information in the short and/or long term), information processing (dealing with information gathered by the five senses), visuospatial function (visual perception, depth perception, using mental imagery, copying drawings, constructing objects or shapes), producing and understanding language, verbal fluency (word- finding), solving problems, making decisions, and executive functions (planning and prioritizing).
  • cognitive decline it is meant a progressive decrease in one or more of these abilities, e.g., a decline in memory, language, thinking, judgment, etc.
  • an impairment in cognitive ability and “cognitive impairment,” it is meant a reduction in cognitive ability relative to a healthy individual, e.g., an age-matched healthy individual, or relative to the ability of the individual at an earlier point in time, e.g., 2 weeks, 1 month, 2 months, 3 months, 6 months, 1 year, 2 years, 5 years, or 10 years or more previously.
  • chemotherapy induced cognitive disorder e.g., chemotherapy induced cognitive impairment
  • an impairment in cognitive ability that is typically associated with chemotherapy, e.g., platinum based chemotherapy, e.g., cisplatin therapy.
  • a blood product comprising plasma components is administered to an individual in need thereof, e.g., an individual suffering or at risk of suffering from a chemotherapy induced cognitive disorder, e.g., CICI.
  • methods according to embodiments of the invention including administering a blood product comprising plasma components from an individual (the "donor individual”, or “donor") to an individual at least at risk of suffering or suffering from chemotherapy induced cognitive disorder, e.g., CICI (the "recipient individual” or “recipient”).
  • a blood product comprising plasma components it is meant any product derived from blood that comprises plasma (e.g. whole blood, blood plasma, or fractions thereof).
  • Non-limiting examples of plasma-comprising blood products suitable for use in the subject methods include whole blood treated with anti-coagulant (e.g., EDTA, citrate, oxalate, heparin, etc.), blood products produced by filtering whole blood to remove white blood cells ("leukoreduction"), blood products consisting of plasmapheretically-derived or apheretically- derived plasma, fresh-frozen plasma, blood products consisting essentially of purified plasma, and blood products consisting essentially of plasma fractions.
  • anti-coagulant e.g., EDTA, citrate, oxalate, heparin, etc.
  • blood products produced by filtering whole blood to remove white blood cells (“leukoreduction")
  • blood products consisting of plasmapheretically-derived or apheretically- derived plasma fresh-frozen plasma
  • blood products consisting essentially of purified plasma and blood products consisting essentially of plasma fractions.
  • plasma product that is employed is a non-whole blood plasma product, by which is meant that the product is not whole blood, such that it lacks one or more components found in whole blood, such as erythrocytes, leukocytes, etc., at least to the extent that these components are present in whole blood.
  • the plasma product is substantially, if not completely, acellular, where in such instances the cellular content may be 5% by volume or less, such as 1 % or less, including 0.5% or less, where in some instances acellular plasma fractions are those compositions that completely lack cells, i.e., they include no cells.
  • Collection of blood products comprising plasma components.
  • Embodiments of the methods described herein include administration of blood products comprising plasma components which can be derived from donors, including human volunteers.
  • the term, “human-derived” can refer to such products.
  • Methods of collection of plasma comprising blood products from donors are well-known in the art. (See, e.g., AABB TECHNICAL MANUAL, (Mark A. Fung, et al., eds., 18th ed. 2014), herein incorporated by reference).
  • donations are obtained by venipuncture.
  • the venipuncture is only a single venipuncture.
  • no saline volume replacement is employed.
  • the process of plasmapheresis is used to obtain the plasma comprising blood products.
  • Plasmapheresis can comprise the removal of a weight-adjusted volume of plasma with the return of cellular components to the donor.
  • sodium citrate is used during plasmapheresis in order to prevent cell clotting.
  • the volume of plasma collected from a donor is preferably between 690 to 880 mL after citrate administration, and preferably coordinates with the donor’ s weight.
  • An embodiment of the methods described herein includes the administration of plasma fractions to a subject. Fractionation is the process by which certain protein subsets are separated from plasma. Fractionation technology is known in the ail and relies on steps developed by Cohn et al. during the 1940s. (E. Cohn, Preparation and properties of serum and plasma proteins. IV. A system for the separation into fractions of the protein and lipoprotein components of biological tissues and fluids. 68 J Am Chem Soc 459 (1946), herein incorporated by reference). Several steps are involved in this process, each step involving specific ethanol concentrations as well as pH, temperature, and osmolality shifts which result in selective protein precipitation. Precipitates are also separated via centrifugation or precipitation.
  • each fraction (or effluent from a prior separation step) contains or potentially contains therapeutically-useful protein fractions.
  • fractionation has reached further complexity, and as such, comprises additional embodiments of the invention.
  • This recent increase in complexity has occurred through: the introduction of chromatography resulting in isolation of new proteins from existing fractions like cryoprecipitate, cryo-poor plasma, and Cohn fractions; increasing IgG recovery by integrating chromatography and the ethanol fractionation process; and viral reduction/inactivation/removal.
  • anion-exchange chromatography can be utilized. This preserves functional activity of proteins and/or protein fractions.
  • Heparin and monoclonal antibodies are also used in affinity chromatography.
  • blood plasma is fractionated in an industrial setting. Frozen plasma is thawed at 1°C to 4°C. Continuous refrigerated centrifugation is applied to the thawed plasma and cryoprecipitate isolated. Recovered cryoprecipitate is frozen at -30°C or lower and stored. The cryoprecipitate-poor (“cryo-poor”) plasma is immediately processed for capture (via, for example, primary chromatography) of labile coagulation factors such as factor IX complex and its components as well as protease inhibitors such as antithrombin and Cl esterase inhibitor. Serial centrifugation and precipitate isolation can be applied in subsequent steps.
  • the blood plasma fraction may be one in which substantially all the clotting factors are removed in order to retain the efficacy of the fraction with reduced risk of thromboses.
  • the plasma fraction may be a plasma fraction as described in United States Patent No. 62/376,529 filed on August 18, 2016; the disclosure of which is incorporated by reference in its entirety herein.
  • PPF plasma protein fraction
  • HAS human albumin solution
  • PPF can be produced from a plasma using a manufacturing process that uses acetone. PPF can also be produced from plasma using a manufacturing process that does not use acetone.
  • the total protein in the final product shall consist of at least 83 percent albumin, and no more than 17 percent globulins. No more than 1 percent of the total protein shall be gamma globulin.
  • the protein composition is determined by a method that has been approved for each manufacturer by the Director, Center for Biologies Evaluation and Research, Food and Drug Administration.
  • PPF Protein Fraction
  • Hink, J.H., Jr., et al., Preparation and Properties of a Heat-Treated Human Plasma Protein Fraction, Vox SANGUINIS 2(174) (1957) can also refer to a solid form, which when suspended in solvent, has similar composition.
  • the total globulin fraction can be determined through subtracting the albumin from the total protein.
  • albumin Human
  • albumin (Human) also referred to herein as “HAS” is the proper name of the product defined as “sterile solution of the albumin derived from human plasma.”
  • CFR Code of Federal Regulations “CFR” 21 CFR 640.80 which is herein incorporated by reference.
  • the source material for Albumin (Human) is plasma recovered from Whole Blood prepared as prescribed in 21 CFR 640.1-640.5 (incorporated by reference herein), or Source Plasma prepared as prescribed in 21 CFR 640.60-640.76 (incorporated by reference herein).
  • Other requirements for Albumin (Human) are listed in 21 CFR 640.80 - 640.84 (incorporated by reference herein).
  • albumin Human
  • HAS refers to a to a sterile solution of protein composed of albumin and globulin, derived from human plasma, with an albumin content of at least 95%, with no more than 5% globulins (including al , a2, , and y globulins) and other plasma proteins.
  • HAS can also refer to a solid form, which when suspended in solvent, has similar composition. The total globulin fraction can be determined through subtracting the albumin from the total protein.
  • the blood product can be derived from a young donor or pool of young donors, and can be rendered devoid of IgM in order to provide a young blood product that is ABO compatible.
  • IgM appears to be responsible for transfusion reactions when patients are given plasma that is not ABO matched. Removal of IgM from blood products or fractions helps eliminate transfusion reactions in subjects who are administered the blood products and blood plasma fractions of the invention.
  • the invention is directed to a method of treating or preventing a chemotherapy induced cognitive disorder, e.g., chemotherapy induced cognitive impairment or neurodegeneration in a subject.
  • the method comprises: administering to the subject a blood product or blood fraction derived from whole-blood from an individual or pool of individuals, wherein the blood product or blood fraction is substantially devoid of (a) at least one clotting factor and/or (b) IgM.
  • the individual(s) from whom the blood product or blood fraction is derived are young individuals.
  • the blood product is substantially devoid of at least one clotting factor and IgM.
  • the blood product is substantially devoid of fibrinogen (Factor I).
  • the blood product substantially lacks erythrocytes and/or leukocytes.
  • the blood product is substantially acellular.
  • the blood product is derived from plasma.
  • Additional embodiments of the invention use plasma fractions with reduced albumin concentration compared to PPF, but with increased amounts of globulins and other plasma proteins (what have been re I erred to by some as “contaminants”).
  • the embodiments, as with PPF, HAS, Effluent I, and Effluent II/III are all effectively devoid of clotting factors.
  • Such plasma fractions are hereinafter referred to as “protein-enriched plasma protein products.”
  • an embodiment of the invention may use a protein-enriched plasma protein product comprised of 82% albumin and 18% a, p, and y globulins and other plasma proteins.
  • Another embodiment of the invention may use a protein-enriched plasma protein product comprised of 81% albumin and 19% of a, , and y globulins and/or other plasma proteins.
  • Another embodiment of the invention may use a protein-enriched plasma protein product comprised of 80% albumin and 20% of a, p, and y globulins and/or other plasma proteins.
  • Additional embodiments of the invention may use protein-enriched plasma protein products comprised of 70-79% albumin and a corresponding 21- 30% of a, P, and y globulins and other plasma proteins.
  • Additional embodiments of the invention may use protein-enriched plasma protein products comprised of 60-69% albumin and a corresponding 31-40% of a, p, and y globulins and other plasma proteins.
  • Additional embodiments of the invention may use protein-enriched plasma protein products comprised of 50-59% albumin and a corresponding 41-50% of a, P, and y globulins and other plasma proteins. Additional embodiments of the invention may use protein-enriched plasma protein products comprised of 40- 49% albumin and a corresponding 51-60% of a, P, and y globulins and other plasma proteins. Additional embodiments of the invention may use protein-enriched plasma protein products comprised of 30-39% albumin and a corresponding 61-70% of a, p, and y globulins and other plasma proteins.
  • Additional embodiments of the invention may use protein-enriched plasma protein products comprised of 20-29% albumin and a corresponding 71-80% of a, P, and y globulins and other plasma proteins. Additional embodiments of the invention may use protein- enriched plasma protein products comprised of 10-19% albumin and a corresponding 81-90% of a, P, and y globulins and other plasma proteins. Additional embodiments of the invention may use protein-enriched plasma protein products comprised of 1-9% albumin and a corresponding 91- 99% of a, P, and y globulins and other plasma proteins. A further embodiment of the invention may use protein-enriched plasma protein products comprised of 0-1% albumin and 99-100% of a, P, and y globulins and other plasma proteins.
  • Embodiments of the invention described above may also have total gamma globulin concentrations of 0-5%.
  • the specific concentrations of proteins in a plasma fraction may be determined using techniques well-known to a person having ordinary skill in the relevant art.
  • such techniques include electrophoresis, mass spectrometry, ELISA analysis, and Western blot analysis.
  • An embodiment of the invention allows for blood used in the preparation of human plasma protein fraction to be collected in flasks with citrate or anticoagulant citrate dextrose solution for inhibition of coagulation, with further separation of Fractions I, II + III, IV, and PPF as per the method disclosed in Hink el al. (See Hink, J.H., Jr., el al., Preparation and Properties of a Heat-Treated Human Plasma Protein Fraction, Vox SANGUINIS 2(174) (1957), herein incorporated by reference.)
  • the mixture can be collected to 2 - 8 °C.
  • the plasma can then subsequently be separated by centrifugation at 7°C, removed, and stored at -20°C.
  • the plasma can then be thawed at 37°C and fractionated, preferably within eight hours after removal from -20°C storage.
  • Plasma can be separated from Fraction I using 8% ethanol at pH 7.2 and a temperature at -2 to -2.5°C with protein concentration of 5.1 to 5.6 percent.
  • Cold 53.3 percent ethanol (176 mL/L of plasma) with acetate buffer (200 mL 4M sodium acetate, 230 mL glacial acetic acid quantum satis to 1 L with H2O) can be added using jets at a rate, for example, of 450 mL/minute during the lowering the plasma temperature to -2°C.
  • Fraction I can be separated and removed from the effluent (Effluent I) through ultracentrifugation. Fibrinogen can be obtained from Fraction I as per methods well-known to those having ordinary skill in the art.
  • Fraction II + III can be separated from Effluent I through adjustment of the effluent to 21 percent ethanol at pH 6.8, temperature at -6°C, with protein concentration of 4.3 percent.
  • Cold 95 percent ethanol (176 mL/L of Effluent I) with 10 M acetic acid used for pH adjustment can be added using jets at a rate, for example, of 500 mL/minute during the lowering of the temperature of Effluent I to -6°C.
  • the resulting precipitate (Fraction II + III) can be removed by centrifugation at -6°C.
  • Gamma globulin can be obtained from Fraction II + III using methods well-known to those having ordinary skill in the ait.
  • Fraction IV- 1 can be separated from Effluent II + III (“Effluent I FI II”) through adjustment of the effluent to 19 percent ethanol at pH 5.2, temperature at -6°C, and protein concentration of 3 percent. H2O and 10 M acetic acid used for pH adjustment can be added using jets while maintaining Effluent II/III at -6°C for 6 hours. Precipitated Fraction VI- 1 can be settled at -6°C for 6 hours and subsequently separated from the effluent by centrifugation at the same temperature. Stable plasma protein fraction can be recovered from Effluent IV- 1 through adjustment of the ethanol concentration to 30 percent at pH 4.65, temperature -7°C and protein concentration of 2.5 percent.
  • Effluent IV- 1 This can be accomplished by adjusting the pH of Effluent IV- 1 with cold acid- alcohol (two pails 2 M acetic acid and one part 95 percent ethanol). While maintaining a temperature of - 7°C, to every liter of adjusted Effluent IV-1 170 mL cold ethanol (95%) is added. Proteins that precipitate can be allowed to settle for 36 hours and subsequently removed by centrifugation at - 7°C.
  • the recovered proteins can be dried (e.g. by freeze drying) to remove alcohol and H2O.
  • the resulting dried powder can be dissolved in sterile distilled water, for example using 15 liters of water/kg of powder, with the solution adjusted to pH 7.0 with 1 M NaOH.
  • a final concentration of 5 per cent protein can be achieved by adding sterile distilled water containing sodium acetyl tryptophanate, sodium caprylate, and NaCl, adjusting to final concentrations of 0.004 M acetyl tryptophanate, 0.004 M caprylate, and 0.112 M sodium.
  • the solution can be filtered at 10°C to obtain a clear solution and subsequently heat-treated for inactivation of pathogens at 60°C for at least 10 hours.
  • Effluents I or Effluent II/III may be utilized to treat such diseases as cognitive and neurodegenerative disorders and are embodiments of the invention.
  • PPF blood plasma fractions and plasma protein fraction
  • pH, temperature, and ethanol concentration among other things can be adjusted to produce different variations of plasma fractions and plasma protein fraction in the different embodiments and methods of the invention.
  • additional embodiments of the invention contemplate the use of nanofiltration for the removal/inactivation of pathogens from plasma fractions and plasma protein fraction.
  • An additional embodiment of the invention contemplates methods and composition using and/or comprising additional blood plasma fractions.
  • the invention demonstrates that specific concentrations of albumin are not critical for improving cognitive activity.
  • fractions with reduced albumin concentration such as those fractions having below 83% albumin, are contemplated by the invention.
  • aspects of the methods described herein include treatment of a subject with a plasma comprising blood product, such as a blood plasma fraction, e.g., fractions as described above.
  • An embodiment includes treatment of a human subject with a plasma comprising blood product.
  • methods of treatment of subjects with plasma comprising blood products are recognized in the art.
  • one embodiment of the methods of the inventions described herein is comprised of administering fresh frozen plasma to a subject for treatment and/or prevention of chemotherapy induced cognitive disorder, e.g., CICI.
  • the plasma comprising blood product is administered immediately, e.g., within about 12-48 hours of collection from a donor, to the individual suffering or at risk from chemotherapy induced cognitive disorder, e.g., CICI.
  • the product may be stored under refrigeration, e.g., 0- 10°C.
  • fresh frozen plasma is one that has been stored frozen (cryopreserved) at -18°C or colder. Prior to administration, the fresh frozen plasma is thawed and once thawed, administered to a subject 60-75 minutes after the thawing process has begun.
  • Each subject preferably receives a single unit of fresh frozen plasma (200-250 mL), the fresh frozen plasma preferably derived from donors of a pre-determined age range.
  • the fresh frozen plasma is donated by (derived from) young individuals.
  • the fresh frozen plasma is donated by (derived from) donors of the same gender.
  • the fresh frozen plasma is donated by (derived from) donors of the age range between 18-22 years old.
  • subjects are treated twice per week with 3-4 days between infusions. In an embodiment of the invention, treatment persists until a specific endpoint is reached.
  • the plasma comprising blood products are screened after donation by blood type.
  • the plasma comprising blood products are screened for infectious disease agents such as HIV I & II, HBV, HCV, HTLV I & II, anti-HBc per the requirements of 21 CFR 640.33 and recommendations contained in FDA guidance documents.
  • the subject is treated with a “Plasma Fraction.”
  • the Plasma Fraction is PPF or HAS.
  • the Plasma Fraction is one of the Commercial PPF Preparations of the Commercial HAS Preparations.
  • the Plasma Fraction is a PPF or HAS derived from a pool of individuals of a specific age range, such as young individuals, or is a modified PPF or HAS fraction which has been subjected to additional fractionation or processing (e.g. PPF or HAS with one or more specific proteins partially or substantially removed).
  • the Plasma Fraction is an IGIV plasma fraction which has been substantially depleted of immune globulin (IgG).
  • a blood fraction which is “substantially depleted” or which has specific proteins “substantially removed,” such as IgG refers to a blood fraction containing less than about 50% of the amount that occurs in the reference product or whole blood plasma, such as less than 45%, 40%, 35%, 30%, 25%, 20%, 15%, 5%, 4%, 3%, 2%, 1%, 0.5%, .25%, .1%, undetectable levels, or any integer between these values, as measured using standard assays well known in the art.
  • Another aspect of the present invention relates to methods of monitoring the effect of a medication on a subject for treating chemotherapy induced cognitive disorder, e.g., CICI, the method comprising comparing cognitive function before and after treatment.
  • chemotherapy induced cognitive disorder e.g., CICI
  • the method may comprise evaluation of cognitive function based on medical history, family history, physical and neurological examinations by clinicians who specialize dementia and cognitive function, laboratory tests, and neuropsychological assessment.
  • Additional embodiments which are contemplated by the invention include: the assessment of consciousness, such as using the Glasgow Coma Scale (EMV); mental status examination, including the abbreviated mental test score (AMTS) or minimental state examination (MMSE) (Folstein et al., J. Psychiatr. Res 1975; 12:1289-198); global assessment of higher functions; estimation of intracranial pressure such as by fundoscopy.
  • EMV Glasgow Coma Scale
  • AMD abbreviated mental test score
  • MMSE minimental state examination
  • examinations of peripheral nervous system may be used to evaluate cognitive function, including any one of the followings: sense of smell, visual fields and acuity, eye movements and pupils (sympathetic and parasympathetic), sensory function of face, strength of facial and shoulder girdle muscles, hearing, taste, pharyngeal movement and reflex, tongue movements, which can be tested individually (e.g. the visual acuity can be tested by a Snellen chart; a reflex hammer used testing reflexes including masseter, biceps and triceps tendon, knee tendon, ankle jerk and plantar (i.e. Babinski sign); Muscle strength often on the MRC scale 1 to 5; Muscle tone and signs of rigidity.
  • a blood plasma fraction is administered to the subject.
  • the blood plasma fraction is administered by intravenous infusion.
  • the rate of infusion may vary, but in one embodiment of the invention, the infusion rate is 5-8 mL/minute. Those having ordinary skill in the art will recognize that the infusion rate can depend upon the subject’s condition and response to administration.
  • an effective dose is the dose that, when administered for a suitable period of time, will slow e.g., by about 20% or more, e.g., by 30% or more, by 40% or more, or by 50% or more, in some instances by 60% or more, by 70% or more, by 80% or more, or by 90% or more, or will halt, cognitive decline in a patient undergoing or having undergone chemotherapy.
  • an effective amount or dose of blood product will not only slow or halt the progression of the chemotherapy induced cognitive disorder, e.g., CICI but will also induce the reversal of the condition, i.e., will cause an improvement in cognitive ability.
  • an effective amount is the amount that when administered for a suitable period of time, usually at least about one week, and maybe about two weeks, or more, up to a person of about 3 weeks, 4 weeks, 8 weeks, or longer will improve the cognitive abilities of an individual suffering from a chemotherapy induced cognitive disorder, e.g., CICI, by, for example, 1.5-fold, 2-fold, 3-fold, 4- fold, 5-fold, in some instances 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold or more relative to cognition prior to administration of the blood product or fraction.
  • a chemotherapy induced cognitive disorder e.g., CICI
  • an effective amount or dose of active agent will not only slow or halt the progression of the disease condition but will also induce the reversal of the condition, i.e., will cause an improvement in cognitive function.
  • an effective amount is the amount that when administered for a suitable period of time, will improve the symptoms an individual suffering from chemotherapy induced cognitive disorder, e.g., CICI, for example 1.5-fold, 2-fold, 3-fold, 4-fold, 5-fold, in some instances 6-fold, 7-fold, 8-fold, 9-fold, or 10-fold or more relative to untreated individuals prior to administration of the agent.
  • the blood plasma fraction or Plasma Fraction is administered in accordance with one or more dosing regimens described in U.S. Patent No. 10,357,513, which is herein incorporated by reference in its entirety.
  • an embodiment of the invention includes treating a subject diagnosed with a chemotherapy induced cognitive disorder, e.g., chemotherapy induced cognitive impairment, by administering to the subject an effective amount of blood plasma or Plasma Fraction wherein the blood plasma or Plasma Fraction is administered in a manner resulting in improved cognitive function or neurogenesis after the mean or median half-life of the blood plasma proteins or Plasma Fraction proteins been reached, relative to the most recent administered dose (referred to as “Pulsed Dosing” or “Pulse Dosed” herein).
  • Another embodiment of the invention includes administering the blood plasma or Plasma Fraction via a dosing regimen of at least two consecutive days and monitoring the subject for improved cognitive function at least 3 days after the date of last administration.
  • a further embodiment of the invention includes administering the blood plasma or Plasma Fraction via a dosing regimen of at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 consecutive days and monitoring the subject for improved cognitive function at least 3 days after the date of last administration.
  • Yet another embodiment of the invention includes administering the blood plasma or Plasma Fraction via a dosing regimen of at least 2 consecutive days and after the date of last administration, monitoring for cognitive improvement beyond when the average half-life of the proteins in the blood plasma or Plasma Fraction has been reached.
  • Pulsed Dosing in accordance with the invention includes administration of a first set of doses, e.g., as described above, followed by a period of no dosing, e.g., a "dosing-free period", which in turn is followed by administration of another dose or set of doses.
  • the duration of this " dosing-free" period may vary, but in some embodiments, is 7 days or longer, such as 10 days or longer, including 14 days or longer, wherein some instances the dosing-free period ranges from 15 to 365 days, such as 30 to 90 days and including 30 to 60 days.
  • embodiments of the methods include non-chronic (i.e., non- continuous) dosing, e.g., non-chronic administration of a blood plasma product.
  • the pattern of Pulsed Dosing followed by a dosing-free period is repeated for a number of times, as desired, where in some instances this pattern is continued for 1 year or longer, such as 2 years or longer, up to and including the life of the subject.
  • Another embodiment of the invention includes administering the blood plasma or Plasma Fraction via a dosing regimen of 5 consecutive days, with a dosing-free period of 2-3 days, followed by administration for 2-14 consecutive days.
  • an “effective amount” or “effective dose” of active agent is meant an amount of active agent that will inhibit, antagonize, decrease, reduce, or suppress by about 20% or more, e.g., by 30% or more, by 40% or more, or by 50% or more, in some instances by 60% or more, by 70% or more, by 80% or more, or by 90% or more, in some cases by about 100%, i.e., to negligible amounts, and in some instances, reverse the progression of the chemotherapy induced cognitive disorder, e.g., CICI.
  • a plasma fraction is administered to the subject.
  • the Plasma Fraction is plasma protein fraction (PPF).
  • PPF is selected from the Commercial PPF Preparations.
  • the PPF is comprised of 88% normal human albumin, 12% alpha and beta globulins and not more than 1% gamma globulin as determined by electrophoresis.
  • Embodiments of this embodiment used in practicing methods of the invention include, for example, this embodiment as a 5% solution of PPF buffered with sodium carbonate and stabilized with 0.004 M sodium caprylate and 0.004 M acetyltryptophan. Additional formulations, including those modifying the percentage of PPF (e.g. about 1% to about 10%, about 10% to about 20%, about 20% to 25%, about 25% to 30%) in solution as well as the concentrations of solvent and stabilizers may be utilized in practicing methods of the invention.
  • An embodiment of invention includes administering a blood plasma fraction or a Plasma Fraction derived from the plasma of individuals of certain age ranges. Additional embodiments include administering a plasma protein fraction derived from the plasma of individuals of certain age ranges. An embodiment includes administering a PPF or a HAS which has been derived from the plasma of young individuals. In another embodiment of the invention the young individuals are of a single specific age or a specific age range. In yet another embodiment, the average age of the donors is less than that of the subject or less than the average age of the subjects being treated.
  • Certain embodiments of the invention include pooling blood or blood plasma from individuals of specific age ranges and fractionating the blood plasma as described above to attain a plasma protein fraction product such as PPF or HAS.
  • a plasma protein fraction product such as PPF or HAS.
  • the plasma protein fraction or specific plasma protein fraction is attained from specific individuals fitting a specified age range.
  • the blood plasma fraction, Plasma Fraction, or specific plasma protein fraction product is attained from a pool of young individuals, of which “young” may be determined by chronologic or biologic age as described above, and the age(s) of the individuals may be a specific age or age range.
  • the subject methods and plasma-comprising blood products and fractions find use in treating, including preventing, chemotherapy induced cognitive disorders, e.g., CICI.
  • Individuals suffering from or at risk of developing a chemotherapy induced cognitive disorder, e.g., impairment, that will benefit from treatment with the subject plasma-comprising blood product, e.g., by the methods disclosed herein, include individuals of any age that, where the individual are undergoing, or have undergone, a chemotherapeutic treatment regiment, where in some instances the individuals are about 0.5 years or older, e.g., 1 year or older, e.g., 2 years or older, e.g., 5 years or older, e.g., 10 years or older, e.g., 15 years or older, e.g., 20 years or older, e.g., 25 years or older, e.g., 30 years or older, e.g., 35 years or older, e.g., 40 years or older, e.g., 45 years or older, e.g., 50 year’s old or older, e.g., 60 year’s old or older, 70 years old or older,
  • Subject treated in accordance with embodiments of the invention are those subjects undergoing, or having undergone, a chemotherapy regiment. Accordingly, the subject those that have been administered a chemotherapeutic agent one or more times, e.g., to treat the subject for a neoplastic disease condition, e.g., cancer. As such, subjects treated in accordance with embodiments of the invention are those that have been diagnosed as having a neoplastic disease, c.g., cancer, and been administered a chemotherapeutic agent for the treatment thereof.
  • Chemotherapeutic agents are non-peptidic (i.e., non-proteinaceous) compounds that reduce proliferation of cancer cells, and encompass cytotoxic agents and cytostatic agents.
  • Non-limiting examples of chemotherapeutic agents include alkylating agents, nitrosoureas, antimetabolites, antitumor antibiotics, plant (vinca) alkaloids, and steroid hormones.
  • agents that act to reduce cellular proliferation include alkylating agents, such as nitrogen mustards, nitrosoureas, ethylenimine derivatives, alkyl sulfonates, and triazenes, including, but not limited to, mechlorethamine, cyclophosphamide (CytoxanTM), melphalan (L-sarcolysin), carmustine (BCNU), lomustine (CCNU), semustine (methyl-CCNU), streptozocin, chlorozotocin, uracil mustard, chlormethine, ifosfamide, chlorambucil, pipobroman, triethylenemelamine, triethylenethiophosphoramine, busulfan, dacarbazine, and temozolomide.
  • alkylating agents such as nitrogen mustards, nitrosoureas, ethylenimine derivatives, alkyl sulfonates, and triazenes, including, but not limited to, mechloreth
  • Antimetabolite agents include folic acid analogs, pyrimidine analogs, purine analogs, and adenosine deaminase inhibitors, including, but not limited to, cytarabine (CYTOSAR-U), cytosine arabinoside, fluorouracil (5-FU), floxuridine (FudR), 6-thioguanine, 6-mercaptopurine (6-MP), pentostatin, 5 -fluorouracil (5-FU), methotrexate, 10-propargyl-5,8-dideazafolate (PDDF, CB3717), 5, 8 -dideazatetrahydrofolic acid (DDATHF), leucovorin, fludarabine phosphate, pentostatine, and gemcitabine.
  • CYTOSAR-U cytarabine
  • cytosine arabinoside including, but not limited to, fluorouracil (5-FU), floxuridine (FudR), 6-thioguanine,
  • anti-proliferative cytotoxic agents are navelbene, CPT-11, anastrazole, letrazole, capecitabine, reloxafine, cyclophosphamide, ifosamide, and droloxafine.
  • Microtubule affecting agents that have antiproliferative activity are also suitable for use and include, but arc not limited to, allocolchicinc (NSC 406042), Halichondrin B (NSC 609395), colchicine (NSC 757), colchicine derivatives (e.g., NSC 33410), dolstatin 10 (NSC 376128), maytansine (NSC 153858), rhizoxin (NSC 332598), paclitaxel (Taxol®), Taxol® derivatives, docetaxel (Taxotere®), thiocolchicine (NSC 361792), trityl cysterin, vinblastine sulfate, vincristine sulfate, natural and synthetic epothilones including but not limited to, eopthilone A, epothilone B, discodermolide; estramustine, nocodazole, and the like.
  • mycophenolic acid mycophenolic acid, thalidomide, desoxyspergualin, azasporine, leflunomide, mizoribine, azaspirane (SKF 105685); Iressa® (ZD 1839, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-(3-(4- morpholiny l)propoxy )quinazoline) ; etc .
  • the methods comprise treating or preventing chemotherapy-induced cognitive disorder in a subject that has been administered a metal complex chemotherapeutic agent, such as a platinum complex chemotherapeutic agent, e.g., CisPt, CarboPt, and/or OxaliPt.
  • a metal complex chemotherapeutic agent such as a platinum complex chemotherapeutic agent, e.g., CisPt, CarboPt, and/or OxaliPt.
  • the subject methods and compositions find use in slowing the progression of the chemotherapy induced cognitive disorder, e.g., CICI.
  • the subject methods of treatment include measuring the progression of cognitive decline after treatment, and determining that the progression of cognitive decline is reduced.
  • the determination is made by comparing to a reference, e.g., the rate of cognitive decline in the individual prior to treatment, e.g., as determined by measuring cognition prior at two or more time points prior to administration of the subject blood product.
  • the subject methods and compositions also find use in stabilizing the cognitive abilities of an individual, e.g., an individual suffering from chemotherapy induced cognitive disorder, e.g., CICI, or an individual at risk of suffering from chemotherapy induced cognitive disorder, e.g., CICI.
  • an individual may demonstrate some chemotherapy induced cognitive disorder, e.g., CICI, and progression of cognitive impairment observed prior to treatment with the disclosed methods will be halted following treatment by the disclosed methods.
  • the individual may be at risk for developing chemotherapy induced cognitive disorder, e.g., CICI (e.g., the individual may be undergoing and have undergone a chemotherapy regiment), and the cognitive abilities of the individual are substantially unchanged, i.e., no cognitive decline can be detected, following treatment by the disclosed methods as compared to prior to treatment with the disclosed methods.
  • CICI chemotherapy induced cognitive disorder
  • the cognitive abilities of the individual are substantially unchanged, i.e., no cognitive decline can be detected, following treatment by the disclosed methods as compared to prior to treatment with the disclosed methods.
  • the subject methods and compositions also find use in reducing cognitive impairment in an individual suffering from a chemotherapy induced cognitive disorder, e.g., chemotherapy induced cognitive impairment.
  • cognitive ability is improved in the individual following treatment by the subject methods.
  • the cognitive ability in the individual is increased, e.g., by 2-fold or more, 5-fold or more, 10-fold or more, 15-fold or more, 20-fold or more, 30-fold or more, or 40-fold or more, including 50-fold or more, 60-fold or more, 70-fold or more, 80-fold or more, 90-fold or more, or 100-fold or more, following treatment by the subject methods relative to the cognitive ability that is observed in the individual prior to treatment by the subject methods.
  • treatment by the subject methods and compositions restores the cognitive ability in the individual suffering from a chemotherapy induced cognitive disorder, e.g., chemotherapy induced cognitive impairment.
  • the following types of assessments arc used alone or in combination with subjects suffering from a chemotherapy induced cognitive disorder, as desired.
  • the following types of methods are presented as examples and are not limited to the recited methods. Any convenient methods to monitor disease may be used in practicing the invention, as desired. Those methods are also contemplated by the methods of the invention.
  • Embodiments of the methods of the invention further comprise methods of monitoring the effect of a medication or treatment on a subject for treating cognitive impairment and/or age- related dementia, the method comprising comparing cognitive function before and after treatment.
  • the method may comprise evaluation of cognitive function based on medical history, family history, physical and neurological examinations by clinicians who specialize dementia and cognitive function, laboratory tests, and neuropsychological assessment.
  • examinations of peripheral nervous system may be used to evaluate cognitive function, including any one of the followings: sense of smell, visual fields and acuity, eye movements and pupils (sympathetic and parasympathetic), sensory function of face, strength of facial and shoulder girdle muscles, hearing, taste, pharyngeal movement and reflex, tongue movements, which can be tested individually (e.g. the visual acuity can be tested by a Snellen chart; a reflex hammer used testing reflexes including masseter, biceps and triceps tendon, knee tendon, ankle jerk and plantar (i.e. Babinski sign); Muscle strength often on the MRC scale 1 to 5; Muscle tone and signs of rigidity.
  • reagents, devices, and kits thereof for practicing one or more of the above-described methods.
  • the subject reagents, devices, and kits thereof may vary greatly.
  • each container of the kit contains a blood plasma product from a donor of substantially the same age, i.e., all of the containers include product from donors that are substantially the same, if not the same, age.
  • substantially the same age is meant that the various donors from which the blood plasma products of the kits are obtained differ in each, in some instances, by 5 years or less, such as 4 year’s or less, e.g., 3 years or less, including 2 years or less, such as 1 year or less, e.g., 9 months or less, 6 months or less, 3 months or less, including 1 month or less.
  • the identifying information can be present on any convenient component of the container, such as a label, an RFID chip, etc.
  • Described herein is the use of a machine learning-based segmentation and quantification approach for aquaporin4 (AQP4) modified from published methodologies and applied to a model of CICI.
  • AQP4 aquaporin4
  • FIGS. 3A-3B show the experimental design and core concept.
  • ROS reactive oxygen species
  • TNFa transforming growth factor
  • FIG. 3B shows the comparison of conventional line scan approach and segmentation detection.
  • line scan AQP4-AF647 signal RSU
  • ROU linear region of interest
  • 10 lines FIG. 3B, top panel
  • 40 pm long segmentation ROI FIG. 3B, bottom panel
  • FIGS. 4A-4C show the histological analysis approach.
  • FIG. 4A shows the 20X images taken with Zeiss Axioscan of entire rostral hippocampus for Hoechst-33342 or nuclear stain (blue), AQP4-AF647 (white), lectin-AF594 (green). Segmentation was performed across the entire CAI stratum radiatum with defined edges at the inferior stratum lacunosum-molccularc and superior pyramidal layer. White boxes denote location of 100% zoom representative images. (FIGS. 4B- 4C).
  • FIG. 4B shows 100% zoomed region of representative image taken from CAI .
  • In maliciousis segmentation tool was trained off representative single channel images for lcctin-AF594 to generate a model for detecting blood vessels (BV), segmenting image into vascular region (outlined) and extravascular region.
  • FIG. 4C shows an example of shell analysis mimicking conventional line scan. Rings denote radii from nearest vascular object in 5 pm steps from which target protein AQP4 is measured.
  • FIGS. 5A-5D show total extravascular AQP4 signal by cisplatin treatment.
  • FIG. 5A shows the area in pixels contained in each shell starting at 5 pm to 30 pm from nearest vascular (lectin+) segment at 24 hours, 2 weeks, and 6 weeks post cisplatin treatment. No change was observed in the total extravascular area in each shell.
  • FIG. 5B shows the area under the curve (AUC) generated from line graphs in panel 5A, showing no difference in extravascular area between cisplatin and vehicle treated groups.
  • FIG. 5C shows the cumulative AQP4-AF647 signal across distance, showing a linear increase in total AF647 signal as distance from the nearest vascular signal increases.
  • FIG. 5D shows the AUC generated from cumulative AQP4-AF647 signal shown in panel C, showing an increase of extravascular AQP4 in cisplatin-treated group at 24 hours and 2 weeks that is attenuated at 6 weeks post treatment.
  • FIGS. 6A-6B show cisplatin-induced BBB leakage of sodium fluorescein correlates with extravascular AQP4 signal.
  • FIG. 6A shows that sodium fluorescein (NaF) signal (RFU) was detected in cortex homogenate from 24 hour and 6 week samples as a measurement of extravasation. Increased sodium fluorescein extravasation observed at 24 hours but not 6 weeks post cisplatin treatment.
  • FIG. 6B shows that sodium fluorescein strongly correlated with 20 pm shell AQP4 signal at 24 hours but not 6 weeks, suggesting both factors attenuate by 6 weeks post treatment.
  • FIGS. 7A-7B show that segmentation method detects AQP4 mislocalization up to 2 weeks post-cisplatin treatment.
  • FIG. 7A shows AQP4-AF647 fluorescence (RFU) measured in each 5 pm shell from nearest vascular segment normalized to total area (pixels) contained in the shell (as measured in FIG. 5A).
  • FIG. 7B shows the area under the curve generated from FIG. 7A, demonstrating difference in total extravascular AQP4-AF647 between cisplatin- and vehicle- treated mice across 30 pm.
  • AQP4 mislocalization is observed at 24-hour and 2-week time points but is attenuated by 6 weeks.
  • This Example demonstrates a method of quantifying AQP4 mislocalization as a measurement of astrogliosis and BBB permeability.
  • the approach has expanded the sampling region from a single line extending from the vessel to the total area around all blood vessels and condensing that information into 5 pm bins.
  • the developed approach was used to assess a model of CICI in which various endpoints are attenuated 2 weeks post cisplatin dosing. Across treatment time points, the area contained within each shell was consistent (FIGS. 5A-5D.)
  • the current methodology is based off shells every 5 pm, where line scans can be done on a continuous scale. Granularity can be increased with more layers on a sub 5 pm interval.
  • the two outcomes may be correlated, showing that the BBB dysfunction identified form the methods disclosed herein can be validated using an established method. (FIGS. 6A-6B).
  • the methods disclosed herein can detect the presence of AQP4 mislocalization acutely following cisplatin administration, and this effect is attenuated between 2 weeks and 6 weeks.
  • Example 2 Altered Oligodendrocyte provokeage Contributes to Cisplatin-based Chemotherapy Induced Cognitive Impairment
  • Oligodendrocytes belong to a type of glia cells that undergo lineage progression from oligodendrocyte precursor cells (OPC) to pre- then mature OF.
  • OPC oligodendrocyte precursor cells
  • OE main function is to produce and maintain myelin sheaths.
  • This oligodendrocyte lineage dynamic is crucial for cognitive functions such as learning and memory and demonstrates central nervous system plasticity.
  • OPC differentiation and adaptive myelination by mature OF are regulated by complex transcriptional network that is vital for cognition, as demonstrated by previous studies showing certain stage of lineage progression (such as formation of new mature OEs) to be necessary for certain cognitive tasks like the formation of new memories.
  • CICI adverse neurological sequela
  • OF specific changes have not yet been characterized.
  • metformin was prophylactically administered. Metformin is an AMPK activator that enhances OPC differentiation and myelination. Metformin is also known to prevent CICI.
  • Oxidative stress known to disrupt oligodendrocyte differentiation, was measured to further identify which stage of oligodendrocyte lineage is impacted by cisplatin and metformin.
  • Mice/Treatment Thirty-week-old c57BL/6J male mice (Jackson Labs) were homogenized across treatment groups to home cage nestlet scoring. Mice were injected with 500 pL cisplatin (2.3 mg/kg, I.P.) or sterile PBS for 5-consecutive days, then a subsequent 5-consecutive days of cisplatin or PBS injection with 5 days recovery period between two cycles.
  • An additional cisplatin treatment group received 500 pL Metformin (100 mg/kg, I.P.) for 7-consecutive days starting 1 day prior to cisplatin administration for two cycles while all other groups received an additional 500 pl sterile PBS.
  • Mice were sacrificed 3 days, 14 days, or 42 days post last cisplatin administration. (FIG. 8A.)_At each timepoint (3, 14, and 42 days), a cohort of mice was tested alongside vehicle controls.
  • Histology Heparin perfused hemibrains were collected then PFA drop-fixed. Free floating sections of 30 pm thickness were blocked with donkey serum before incubation with primary antibody solutions. Sections were stained in following dilutions: OLIG2 1:200 (R&D Systems), GPR17 1:200 (Cayman), GST71 1:200 (Bioss).
  • SOD Superoxide Dismutase
  • FIGS. 8A-8C and 9A-9C cisplatin treated mice at each timepoint were normalized to their vehicle control and analyzed using a Mann -Whitney test.
  • FIGS. 10A-10B and 11 cisplatin and cisplatin + Metformin groups at each timepoint were normalized to their vehicle control and analyzed using a Kruskal -Wallis test with Dunn’s post hoc multiple comparisons. All data are represented at mean ⁇ S.E.M. As shown in FTG.
  • cisplatin treatment resulted in a reduction, but not to significant level, of oligodendrocyte population after 3 days that is recovered by 14 days measured by fold change of count per mm 2 quantification of 0LIG2+ cells in hippocampus.
  • cisplatin treatment induces a non-significant but trending reduction in hippocampal oligodendrocytes, although overall changes are restored over time.
  • FIGS. 9A-9C show that cisplatin impact on oligodendrocyte was stage-specific.
  • FIGS. 9A and 9B provide representative 200 pm x 200 pm CAI images demonstrating oligodendrocytes (white), OPCs (red), mature OLs (green), and DAPI (blue). Each arrow indicates a colocalizing cell.
  • FIG. 9C shows that cisplatin treatment resulted in a decrease in OPC population after 3 days that is recovered by 14 days as measured by fold change from vehicle group of count per mm 2 quantification of OLIG2+ cells expressing above threshold GPR17 puncta.
  • FIGS. 10A-10B show that metformin attenuated cisplatin impact on OPC.
  • FIG. 10A shows the fold change from vehicle treatment group of count per mm 2 quantification of OLIG2+, GPR17+, or GSTn-i- cells at 3 days post cisplatin and metformin treatment. Decrease in GPR17+ cells upon
  • FIG. 11 shows that oxidative stress increased in cisplatin-treated mice.
  • SOD plasma level also increased with cisplatin treatment.
  • Oxidative stress increased with cisplatin treatment but returned to baseline level over time.
  • Metformin attenuated oxidative stress level.
  • Oxidative stress level was determined by measurement of SOD concentration in plasma samples. Oxidative stress was significantly increased with cisplatin at 3 days post treatment (**P ⁇ 0.005, Kruskal-Wallis test with Dunn’s post hoc) but not with additional metformin treatment.
  • oxidative stress was significantly increased in both cisplatin treatment group with and without Metformin treatment (***P ⁇ 0.0005 and *P ⁇ 0.05, Kruskal- Wallis test with Dunn’s post hoc) but there was less increase with Metformin treatment. There was no change in oxidative stress level 42 days post last cisplatin treatment.
  • cisplatin treatment induces a non-significant but trending reduction in hippocampal oligodendrocytes, although overall changes are restored over time.
  • OPCs are more vulnerable to cisplatin treatment and may take longer to fully recover compared to mature OLs.
  • prophylactic metformin attenuates cisplatin impact on oligodendrocytes, especially on OPCs. Oxidative stress is increased with cisplatin treatment but is restored over time.
  • oligodendrocytes are arrested at OPC stage upon cisplatin treatment, preventing differentiation of OPC to mature OL.
  • the lack of OPC differentiation is a potential contributor to CICI, which could result in lack of myelin turnover or formation of new oligodendrocyte. Therefore, therapeutically promoting OPC differentiation may mitigate cognitive deficits in CICI.
  • PlasmanateTM PPF PlasmanateTM PPF (Grifols, Clayton, NC), which is also referenced herein as “plasma protein fraction” or PPF.
  • PPF can be produced from a plasma using a manufacturing process that uses acetone.
  • PPF can also be produced from plasma using a manufacturing process that does not use acetone. Additional details about PPF are described above, under Albumin products, “Plasma Protein Fraction (Human) (PPF).”
  • Cisplatin is a platinum-based chemotherapeutic used to treat solid-state tumors as part of the standard treatment for numerous malignancies including head and neck, testicular, gynecologic and non-small cell lung cancer.
  • Nephrotoxicity is an acute concern when using platinum-based compounds, however, neurotoxicity present in both peripheral nerves as well as in the CNS have also been reported.
  • Age- related hippocampal-dependent cognitive deficits are well studied.
  • the hippocampus is well accessed by the vascular system, especially within the subgranular zone of the dentate gyrus (DG), an area of adult neurogenesis, making it an attractive target for evaluation of plasma-derived factors.
  • DG dentate gyrus
  • the benefits are described for a fractionated plasma products, such as PPF to induce reversal of age-related cognitive decline, enhanced hippocampal neurogenesis, reduced neuroinflammation and cell survival in aged immunocompetent mice.
  • mice/Treatment 24 month and 30-week-old C57BL/6J mice (Jackson Labs, strain #0664) were housed in accordance with IACUC. Animals were singly housed under 12-hour light/dark cycle with ad libitum access to food and water. Mice were homogenized across treatment groups according to home cage nestlet scoring, initial body weight, open field distance traveled and % center time. 5-bromo-2'-deoxyuridine (BrdU, Millipore-Sigma) (50 mg/kg) was administered I.P. (intraperitoneally). PPF was administered I.V. (intravenously) at 150 L/day.
  • PrdU 5-bromo-2'-deoxyuridine
  • cisplatin Calbiochem was dosed at 1 mg/kg in sterile-filtered PBS. Immunohistochemistry/Brightfield staining: Heparin/saline perfused brains were collected, PFA drop-fixed hemibrains were sectioned at 30 pm thickness. Counts per animal consisted of average positive cells from 5 sections within the granule cell layer of the DG. Doublccortin (DCX) (EMD Millipore, AB2253) 1:2000, Ki67 (Abeam, abl5580) 1:500.
  • DCX Doublccortin
  • FIGS. 13A-13F shows that 7-day I.V. pulse dosing of PPF partially improved spatial cognition deficit induced by cisplatin.
  • FIG. 13 A in this experimental design: 30- week-old C57BL/6J mice were injected with cisplatin (1 mg/kg, I.P.) or PBS for 5-consecutive days, followed by 5 days recovery period. Then a subsequent 5-consecutive days of cisplatin or PBS dosing (10 mg/kg cisplatin total) was given.
  • FIG. 13B shows the percentage body weight change in cisplatin and PPF+ cisplatin treated mice as compared to vehicle treatment.
  • FIG. 13C shows that the distance travelled in open field test indicates similar locomotor performance between all groups.
  • FIG. 13D shows 2-trial Y-maze layout, training and testing time as well as intertrial interval.
  • FIG. 13E shows the Y-maze % Novel arm time represented as (novel arm time / (novel arm time + familiar arm time) x 100.
  • FIGS. 14A-14G show that PPF moderately attenuated neurogenesis and reduction in proliferation in cisplatin treated mice.
  • FIG. 14A shows that neurogenesis as determined by DCX positive labeled cells within the granule layer of the dentate gyrus in cisplatin, cisplatin + PPF and vehicle treated animals. Significant decrease was observed with cisplatin treatment vs. vehicle.
  • FIG. 14B shows proliferation as measured by Ki67 expressing cells within the primary granule cell layer of the dentate gyrus. Significant decrease was observed with cisplatin treatment vs. vehicle.
  • FIG. 14C shows that plasma cytokine TNFa displays a non- significant increase by cisplatin which is normalized to vehicle concentration by PPF treatment.
  • FIG. 14A shows that neurogenesis as determined by DCX positive labeled cells within the granule layer of the dentate gyrus in cisplatin, cisplatin + PPF and vehicle treated animals. Significant decrease was
  • FIG. 14D shows that plasma cytokine IFNy is non-significantly elevated by cisplatin and normalized by PPF treatment.
  • FIG. 14E shows DCX positive cells (white) within the hippocampus of vehicle treated mice.
  • FIG. 14F shows DCX positive cells (white) within the hippocampus of PPF + cisplatin treated mice and
  • FIG. 14G shows DCX positive cells (white) within the hippocampus of cisplatin treated mice.
  • Cisplatin induces similar dysfunctions in adult mice, thereby allowing for a more robust dynamic range in therapeutic intervention studies. 7-day pulse dosing of PPF in aged WT mice have demonstrated increases in neurogenesis, cell survival and decreased inflammation compared to vehicle treated mice. Therapeutic administration of PPF partially improves spatial cognitive deficits induced by cisplatin administration. Cisplatin administration induces significant reductions in hippocampal neurogenesis and proliferation which therapeutic administration of PPF modestly improves. These data suggest the potential for plasma-derived therapeutics to ameliorate CCI or “brain fog,” for example, CCI or brain fog associated with platinum-derived chemotherapeutic agents.
  • the goal of this study was to evaluate the effects of administration of cisplatin on chronic cognition, neurogenesis, inflammation, proliferation, BBB disfunction and other CNS endpoints in adult C57BL/6 mice and whether PPF can therapeutically attenuate any of these endpoints and the mechanisms involved in such therapeutic effects.

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Abstract

L'invention concerne des procédés et des compositions permettant de traiter des troubles cognitifs induits par la chimiothérapie, par exemple, une déficience cognitive. Les compositions utilisées dans les procédés comprennent le plasma sanguin et des fractions de plasma sanguin dérivées du plasma sanguin avec une efficacité dans le traitement de troubles cognitifs induits par la chimiothérapie.
PCT/US2024/031597 2023-06-13 2024-05-30 Fractions de plasma sanguin en tant que traitement de troubles cognitifs induits par la chimiothérapie Ceased WO2024258622A1 (fr)

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Citations (4)

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WO2016176437A1 (fr) * 2015-04-28 2016-11-03 Newsouth Innovations Pty Limited Ciblage de nad+ pour traiter la déficience cognitive, les neuropathies et l'inactivité induites par la chimiothérapie et la radiothérapie
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