Methods of Using Human Mesenchymal Stem Cells to Effect Cellular and Humoral Immunity
AssigneeLongeveron Inc.
InventorsJoshua M. Hare, Ana Marie Landin
Life of this patent
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Abstract
The present invention provides a method of treating subjects with non-ischemic dilated cardiomyopathy by administering a therapeutically effective amount of an isolated population of allogeneic human mesenchymal stem cells. The present invention also provides a method of treating subjects with symptoms of aging frailty by administering a therapeutically effective amount of an isolated population of allogeneic human mesenchymal stem cells.
Claims42
A method of treating non-ischemic dilated cardiomyopathy in a subject, comprising administering a therapeutically effective amount of a population of isolated allogeneic human mesenchymal stem cells to a subject in need thereof, wherein the number of exhausted B cells (CD19+, CD27−, IgD−) in a sample of the subject's serum decreases by at least 25% as compared to the number of exhausted B cells in a sample of the subject's serum prior to administration of said population of isolated allogeneic human mesenchymal stem cells, thereby treating said non-ischemic dilated cardiomyopathy.
A method of treating non-ischemic dilated cardiomyopathy in a subject, comprising administering a therapeutically effective amount of a population of isolated allogeneic human mesenchymal stem cells to a subject in need thereof, wherein the number of switched memory B cells (CD19+, CD27high, IgD−) in a sample of the subject's serum increases by at least 100% as compared to the number of switched memory B cells in a sample of the subject's serum prior to administration of said population of isolated allogeneic human mesenchymal stem cells, thereby treating said non-ischemic dilated cardiomyopathy.
A method of treating non-ischemic dilated cardiomyopathy in a subject, comprising administering a therapeutically effective amount of a population of isolated allogeneic human mesenchymal stem cells to a subject in need thereof, wherein the number of B-cells expressing intracellular TNF-α in a sample of the subject's serum decreases by at least 30% as compared to the number of B-cells expressing intracellular TNF-α in a sample of the subject's serum prior to administration of said population of isolated allogeneic human mesenchymal stem cells, thereby treating said non-ischemic dilated cardiomyopathy.
A method of treating non-ischemic dilated cardiomyopathy in a subject, comprising administering a therapeutically effective amount of a population of isolated allogeneic human mesenchymal stem cells to a subject in need thereof, wherein the number of early activated T-cells (CD3+, CD69+) in a sample of the subject's serum decreases by at least 30% as compared to the number of early activated T-cells in a sample of the subject's serum prior to administration of said population of isolated allogeneic human mesenchymal stem cells, thereby treating said non-ischemic dilated cardiomyopathy.
A method of treating non-ischemic dilated cardiomyopathy in a subject, comprising administering a therapeutically effective amount of a population of isolated allogeneic human mesenchymal stem cells to a subject in need thereof, wherein the number of chronic activated T-cells (CD3+, CD25+) in a sample of the subject's serum decreases by at least 70% as compared to the number of chronic activated T-Cells in a sample of the subject's serum prior to administration of said population of isolated allogeneic human mesenchymal stem cells, thereby treating said non-ischemic dilated cardiomyopathy.
A method of treating non-ischemic dilated cardiomyopathy in a subject, comprising administering a therapeutically effective amount of a population of isolated allogeneic human mesenchymal stem cells to a subject in need thereof, wherein the number of Temra cells (CD45RA+, CCR7−) in a sample of the subject's serum decreases by at least 40% as compared to the number of Temra cells in a sample of the subject's serum prior to administration of said population of isolated allogeneic human mesenchymal stem cells, thereby treating said non-ischemic dilated cardiomyopathy.
A method of treating non-ischemic dilated cardiomyopathy in a subject, comprising administering a therapeutically effective amount of a population of isolated allogeneic human mesenchymal stem cells to a subject in need thereof, wherein the TNF-α concentration in a sample of the subject's serum decreases by at least 80% as compared to the TNF-α concentration in a sample of the subject's serum prior to administration of said population of isolated allogeneic human mesenchymal stem cells, thereby treating said non-ischemic dilated cardiomyopathy.
A method of treating symptoms of aging frailty in a subject, comprising administering a therapeutically effective amount of a population of isolated allogeneic human mesenchymal stem cells to a subject in need thereof, wherein the number of exhausted B cells (CD19+, CD27−, IgD−) in a sample of the subject's serum decreases by at least 10% as compared to the number of exhausted B cells in a sample of the subject's serum prior to administration of said population of isolated allogeneic human mesenchymal stem cells, thereby treating said symptoms of aging frailty.
A method of treating symptoms of aging frailty in a subject, comprising administering a therapeutically effective amount of a population of isolated allogeneic human mesenchymal stem cells to a subject in need thereof, wherein the number of switched memory B cells (CD 19+, CD27high, IgD−) in a sample of the subject's serum increases by at least 75% as compared to the number of switched memory B cells in a sample of the subject's serum prior to administration of said population of isolated allogeneic human mesenchymal stem cells, thereby treating said symptoms of aging frailty.
A method of treating symptoms of aging frailty in a subject, comprising administering a therapeutically effective amount of a population of isolated allogeneic human mesenchymal stein cells to a subject in need thereof, wherein the number of B-cells expressing intracellular TNF-α in a sample of the subject's serum decreases by at least 60% as compared to the number of B-cells expressing intracellular TNF-α in a sample of the subject's serum prior to administration of said population of isolated allogeneic human mesenchymal stein cells, thereby treating said symptoms of aging frailty,
A method of treating symptoms of aging frailty in a subject, comprising administering a therapeutically effective amount of a population of isolated allogeneic human mesenchymal stein cells to a subject in need thereof, wherein the number of early activated T-cells (CD3+, CD69+) in a sample of the subject's serum decreases by at least 30% as compared to the number of early activated T-cells in a sample of the subject's serum prior to administration of said population of isolated allogeneic human mesenchymal stem cells, thereby treating said symptoms of aging frailty.
A method of treating symptoms of aging frailty in a subject, comprising administering a therapeutically effective amount of a population of isolated allogeneic human mesenchymal stein cells to a subject in need thereof, wherein the number of chronic activated T-cells (CD3+, CD25+) in a sample of the subject's serum decreases by at least 75% as compared to the number of chronic activated T-Cells in a sample of the subject's serum prior to administration of said population of isolated allogeneic human mesenchymal stem cells, thereby treating said symptoms of aging frailty.
A method of treating symptoms of aging frailly in a subject, comprising administering a therapeutically effective amount of a population of isolated allogeneic human mesenchymal stein cells to a subject in need thereof, wherein the number of Temra cells (CD45RA+, CCR7−) in a sample of the subject's serum decreases by at least 20% as compared to the number of Temra cells in a sample of the subject's serum prior to administration of said population of isolated allogeneic human mesenchymal stem cells, thereby treating said symptoms of aging frailty.
A method of treating symptoms of aging frailly in a subject, comprising administering a therapeutically effective amount of a population of isolated allogeneic human mesenchymal stem cells to a subject in need thereof, wherein the TNF-α concentration in a sample of the subject's serum decreases by at least 50% as compared to the TNF-α concentration in a sample of the subject's serum prior to administration of said population of isolated allogeneic human mesenchymal stem cells, thereby treating said symptoms of aging frailty.
A method of treating symptoms of aging frailty in a subject, comprising administering a therapeutically effective amount of a population of isolated allogeneic human mesenchymal stem cells to a subject in need thereof, wherein the CD4+:CD8+ T cell ratio in a sample of the subject's serum increases by at least 100% as compared to the CD41:CD8+ T cell ratio in a sample of the subject's serum prior to administration of said population of isolated allogeneic human mesenchymal stem cells, thereby treating said symptoms of aging frailty.
A method of evaluating cellular and humoral immunity status in a subject, comprising:
- (1) obtaining a serum sample from a subject selected for evaluation based on a determination that the subject was previously in need of treatment of non-ischemic dilated cardiomyopathy and said subject had been administered an initial dose of an isolated population of allogeneic human mesenchymal stem cells,
- (2) performing one or more assays configured to detect a non-ischemic dilated cardiomyopathy marker selected from the group of exhausted B cells (CD19+, CD27−, IgD−), switched memory B cells (CD19+, CD27high, IgD−), B-cells expressing intracellular TNF-α, early activated T-cells (CD3+, CD69+), chronic activated T-cells (CD3+, CD25+), Temra cells (CD45RA+, CCR7−), and serum TNF-α by introducing the serum sample obtained from the subject into an assay instrument which (i) contacts the serum sample with one or more antibodies which specifically bind for detection the biomarker(s) which are assayed, and (ii) generates one or more assay results indicating of binding of each biomarker which is assayed to a respective antibody to provide one or more assay results;
- (3) correlating the assay result(s) generated by the assay instrument to the immunity status of the subject, wherein said correlatimg step comprises assigning a likelihood of one or more future changes in immune status to the subject based on the assay result(s);
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- (4) treating the subject based on the predetermined subpopulation of individuals to which the subject is assigned, wherein the treatment comprises administration of one or more additional doses of an isolated population of allogeneic human mesenchymal stem cells.
A method of evaluating cellular and humoral immunity status in a subject, comprising:
- (1) obtaining a serum sample from a subject selected for evaluation based on a determination that the subject was previously in need of treatment of symptoms of aging frailty and said subject had been administered an initial dose of an isolated population of allogeneic human mesenchymal stem cells;
- (2) performing one or more assays configured to detect aging frailty marker selected from the group of exhausted B cells (CD19+, CD27−, switched memory B cells (CD19+, CD27high, IgD−), B-cells expressing intracellular TNF-α, early activated T-cells (CD3+, CD69+), chronic activated T-cells (CD3+, CD25+), Temra cells (CD45RA+, CCR7−), the CD4+:CD8+ T cell ratio, and serum TNF-α by introducing the serum sample obtained from the subject into an assay instrument which (i) contacts the serum sample with one or more antibodies which specifically bind for detection the biomarker(s) which are assayed, and (ii) generates one or more assay results indicating of binding of each biomarker which is assayed to a respective antibody to provide one or more assay results;
- (3) correlating the assay result(s) generated by the assay instrument to the immunity status of the subject, wherein said correlating step comprises assigning a likelihood of one or more future changes in immune status to the subject based on the assay result(s);
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- (4) treating the subject based on the predetermined subpopulation of individuals to which the subject is assigned, wherein the treatment comprises administration of one or more additional doses of an isolated population of allogeneic human mesenchymal stem cells.
An in vitro method of determining efficacy of treatment of non-ischemic dilated cardiomyopathy in a subject comprising:
- determining the levels of one or more biomarkers selected from the group consisting of exhausted B cells (CD19+, CD27−, IgD−), switched memory B cells (CD19+, CD27high, IgD−), B-cells expressing intracellular TNF-α, early activated T-cells (CD3+, CD69+), chronic activated T-cells (CD3+, CD25+), Temra cells (CD45RA+, CCR7−), and the TNF-α concentration in serum obtained from the subject before and after administration of a population of isolated allogeneic human mesenchymal stem cells to the subject, and comparing the levels of the one or more biomarkers in the serum obtained before and after administration of the population of isolated human mesenchymal stem cells, wherein treatment is efficacious if
- (1) the number of exhausted B cells (CD19+, CD27−, IgD−) decreases by at least 25% as compared to the number of exhausted B cells prior to administration of said population of isolated allogeneic human mesenchymal stem cells,
- (2) the number of switched memory B cells (CD19+, CD27high,IgD−) increases by at least 100% as compared to the number of switched memory B cells prior to administration of said population of isolated allogeneic human mesenchymal stem cells,
- (3) the number of B-cells expressing intracellular TNF-α decreases by at least 30% as compared to the number of B-cells expressing intracellular TNF-α prior to administration of said population of isolated allogeneic human mesenchymal stem cells,
- (4) the number of early activated T-cells (CD3+, CD69+) decreases by at least 30% as compared to the number of early activated T-cells prior to administration of said population of isolated allogeneic human mesenchymal stem cells,
- (5) the number of chronic activated T-cells (CD3+, CD25+) decreases by at least 70% as compared to the number of chronic activated T-Cells prior to administration of said population of isolated allogeneic human mesenchymal stem cells,
- (6) the number of Temra cells (CD45RA+, CCR7−) decreases by at least 40% as compared to the number of Temra cells prior to administration of said population of isolated allogeneic human mesenchymal stem cells, and/or
- (7) the TNF-α concentration in a sample of the subject's serum decreases by at least 80% as compared to the TNF-α concentration in a sample of the subject's serum prior to administration of said population of isolated allogeneic human mesenchymal stem cells.
An in vitro method of determining efficacy of treatment of symptoms of aging frailty in a subject comprising:
- determining the levels of one or more biomarkers selected from the group consisting of exhausted B cells (CD19+, CD27−, IgD−), switched memory B cells (CD19+, CD27high, IgD−), B-cells expressing intracellular TNF-α, early activated T-cells (CD3 +, CD69+), chronic activated T-cells (CD3 +, CD25+), Temra cells (CD45RA+, CCR7−), the CD4+:CD8+ T cell ratio, and the TNF-α concentration in serum obtained from the subject before and after administration of a population of isolated allogeneic human mesenchymal stem cells to the subject, and comparing the levels of the one or more biomarkers in the serum obtained before and after administration of the population of isolated human mesenchymal stem cells, wherein treatment is efficacious if
- (1) the number of exhausted B cells (CD19+, CD27−, IgD−) decreases by at least 10% as compared to the number of exhausted B cells prior to administration of said population of isolated allogeneic human mesenchymal stem cells,
- (2) the number of switched memory B cells (CD19+, CD27high, IgD−) increases by at least 75% as compared to the number of switched memory B cells prior to administration of said population of isolated allogeneic human mesenchymal stem cells,
- (3) the number of B-cells expressing intracellular TNF-α decreases by at least 60% as compared to the number of B-cells expressing intracellular TNF-α prior to administration of said population of isolated allogeneic human mesenchymal stem cells,
- (4) the number of early activated T-cells (CD3+, CD69+) decreases by at least 30% as compared to the number of early activated T-cells prior to administration of said population of isolated allogeneic human mesenchymal stem cells,
- (5) the number of chronic activated T-cells (CD3+, CD25+) decreases by at least 75% as compared to the number of chronic activated T-Cells prior to administration of said population of isolated allogeneic human mesenchymal stem cells,
- (6) the number of Temra cells (CD45RA+, CCR7−) decreases by at least 20% as compared to the number of Temra cells prior to administration of said population of isolated allogeneic human mesenchymal stem cells,
- (7) the TNF-α concentration in a sample of the subject's serum decreases by at least 50% as compared to the TNF-α concentration in a sample of the subject's serum prior to administration of said population of isolated allogeneic human mesenchymal stem cells, and/or
- (8) the CD4+:CD8+ T cell ratio in a sample of the subject's serum increases by at least 100% as compared to the CD4+:CD8+ T cell ratio in a sample of the subject's serum prior to administration of said population of isolated allogeneic human mesenchymal stem cells.
Use in vitro of the levels of exhausted B cells (CD19+, CD27−, IgD−), the levels of switched memory B cells (CD19+, CD27high, IgD−), the levels of B-cells expressing intracellular TNF-α, the levels of early activated T-cells (CD3+, CD69+), the levels of chronic activated T-cells (CD3+, CD25+), the levels of Temra cells (CD45RA+, CCR7−), and the TNF-α concentration in serum for determining whether treatment for non-ischemic dilated cardiomyopathy is efficacious.
Use in vitro of the levels of exhausted B cells (CD19+, CD27−, IgD−), the levels of switched memory B cells (CD19+, CD27high, IgD−), the levels of B-cells expressing intracellular TNF-α, the levels of early activated T-cells (CD3+, CD69+), the levels of chronic activated T-cells (CD3+, CD25+), the levels of Temra cells (CD45RA+, CCR7−), the CD4+:CD8+ T cell ratio, and the TNF-α concentration in serum for determining whether treatment for aging frailty is efficacious.
Dependencies are inferred from the claim text.