CA2505534A1 - Cytotherapeutics, cytotherapeutic units and methods for treatments using them - Google Patents
Cytotherapeutics, cytotherapeutic units and methods for treatments using them Download PDFInfo
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- 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
- A61K35/48—Reproductive organs
- A61K35/51—Umbilical cord; Umbilical cord blood; Umbilical stem cells
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- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0603—Embryonic cells ; Embryoid bodies
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- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/48—Reproductive organs
- A61K35/50—Placenta; Placental stem cells; Amniotic fluid; Amnion; Amniotic stem cells
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- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
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Abstract
The present invention provides cytotherapeutic units comprising predetermine d numbers of selected types of potent cells. Assurance of the nature and identities of such cells is achieved through assay and certification of said numbers and identities. Therapeutic modalities are provided. Libraries of ce ll preparations with assayed and preferably certified populations are preferred and the preparation of cell preparations tailored to specific patients or disease states are provided.
Description
CYTOTHERAPEUTICS, CYTOTHERAPEUTIC UNITS
AND METHODS FOR TREATMENTS USING THEM
FIELD OF THE INVENTION
The present invention is directed to improvements in therapeutics utilizing cytotherapeutic formulations. Cytotherapeutic therapy involves the introduction of immature cells, especially stem cells, into a patient in order to secure palliation, amelioration or cure of a disease state. The present invention is also directed to improved cytotherapeutic agents, to methods of producing them, to unit dosage forms of such agents and to novel paradigms for administering cytotherapeutic units to patients in need of therapy.
BACKGROUND OF THE INVENTION
It has been known heretofore to administer certain types of stem cells to humans and to animals in order to achieve a therapeutic end. Much of this has been done with stem cells from adults, such as those found in adult bone marrow, especially for the repopulation of depopulated interosseous spaces, which attend aggressive chemotherapy or radiation therapy, e.g., for treatment of certain cancers.
Indeed, such cytotherapy has become relatively widespread and has achieved a level of success despite limitations including the lacy of standardization as to cell numbers and types.
Many of these therapeutic regimes employ relatively mature cellular preparations, e.g. bone marrow. While these have a level of therapeutic potential, such cells possess quite a large number of surface antigens and require imrnunosupression attendant to administration. Additionally, most cells extracted from adult bone marrow are limited in the types of cells into which they can differentiate. There have been a number of reports that have indicated that most stem cells isolated from adult bone marrow are only able to differentiate into blood cells.
While this is useful for the treatment of blood related diseases, e.g., leukemia, these cells are not very useful for treating other types of diseases that are localized to a specific type of tissue or organ. An additional problem with bone marrow preparations is that the process of extracting the marrow is often very painful, and although potential donors can be identified many do not consent to the procedure because of the potential for pain and discomfort.
Recently, cytotherapy employing less mature stem cells, such as, for example, those found in neonatal cord blood, has found some success. However, stem cell preparations from most sources, including from neonatal cord blood, include a diverse population of cells with differing potentials for effective therapy and often do not contain a sufficient number of cells for an optimized therapeutic dose, particularly for an averaged size adult undergoing a transplant for leukemia, for example. It is believed that different scientific and medical groups likely achieve differing preparations with differing characteristics, even when supposedly following the same or similar protocols. Presently, most independent preparations, even those done by the same individual, can have different compositions with the specifics of the compositions undetermined. In short, there is a complete laclc of unit to unit reproducibility and little standardization in the cellular units used in transplants.
The foregoing practices can give rise to inconsistent therapeutic outcomes from different research and medical centers and make accurate, statistical analyses for cytotherapeutic procedures difficult or impossible to attain. There is, thus, a long-felt need for improved cytotherapeutic materials and procedures, ones amenable to reproducible outcomes and to scientific analysis. It is also desired to improve specificity of cytotherapeutic treatments and to affect improved efficiencies and outcomes. Importantly, there is also a need for unit to uut reproducibility which may further the ability to collect sufficient data to advance the medical area devoted to cellular therapies. The present invention provides solutions for these and other long-felt needs.
SiJMMARY OF THE INVENTION
As used herein, "cytotherapeutic unit" refers to a cell preparation comprising a plurality of potent cells in which at least one cell type has been tailored for a particular patient or particular disease state. Tailoring may include having a minimum number of said cell type or, alternatively, removal of a portion or all of said cell type.
"Potent," with respect to a cell or cell type, means that the cell or cell type is capable of differentiation into at least one type of cell.
"Pluripotent," with respect to a cell or cell type, means that the cell or cell type is capable of differentiation into at least two different types-of cells.
"Antigenic determinant" refers to the set of antigenic regions on the surface of a cell.
"Factor" refers to a cell type by reference to its antigenic determinant.
Exemplary factors include CD34, CDB, CD10 and the lilce. A cell or cell preparation may also be considered to be positive or negative in regard to a particular factor by reference to whether or not a particular cell or cell type exhibits the characteristics of that particular factor.
The present invention provides for cytotherapeutic units comprising a plurality of potent cells, the contents of which are l~nown with respect to the identities and numbers of at least some of the potent cells. To ensure that the identities and numbers of at least some of the potent cells are accurate at least one assay is performed. In some preferred embodiments, the provider of the unit certifies the accuracy of the assay. In other embodiments, the potent cells for wluch the identities and numbers are known are pluripotent cells. The identities of the potent cells preferably reflect the presence or absence of at least one antigenic determinant on the cells. In some embodiments, the cytotherapeutic unit comprises at least some potent cells exhibiting CD34, CDB, CD10, OCT4, CD38, CXCR4, or CD117, for example. In some embodiments some portion of the cells may also exhibit CD33. In some preferred embodiments, the cytotherapeutic trait comprises cells that lack specific antigenic determinants. In other embodiments, at least one identified potent cell that is derived from a source is specifically excluded or removed from the cellular preparation.
In one embodiment of the invention, some or all cells may be characterized by the presence of one or more of the following cell surface markers: CD10+, CD29+, CD34-, CD38-, CD44+, CD45-, CD54+, CD90+, SH2+, SH3+, SH4+, SSEA3-, SSEA4-, OCT-4+, and ABC-p+.
The potent cells may be obtained from fetal cord blood or other fetal tissue.
In some embodiments, potent cells are obtained from placenta, especially postpartum placenta, which has been metabolically supported and nurtured. Potent cells are preferably obtained from postpartum placenta perfusate. The present invention also provides for cytotherapeutic units wherein the potent cells are derived from a plurality of sources. In some embodiments, the potent cells are derived from at least two individuals, at least five individuals, or at least ten individuals. In some embodiments, the unit comprises at least one cell that is autologous. In some other embodiments, the unit comprises at least one cell that is exogenous. In some embodiments the unit comprises a chimera of autologous and allogeneic cells.
In another embodiment at least some of the cells are genetically modified.
In other embodiments, the plurality of potent cells is selected to render the unit suitable for therapy for an indicated disease state or condition and/or the severity of the condition. In some preferred embodiments, the cytotherapeutic units comprise a minimum number of preselected types of potent cells and may be based, for example, on the weight of the particular patient or that patient's medical status. In some prefeiTed embodiments, the cytotherapeutic unit is assayed to ensure the accuracy of its contents of preselected types of potent cells. In some preferred embodiments, the contents of the preselected potent cells in the cytotherapeutic unit are certified. In other embodiments, the cytotherapeutic unit can be one of a group of substantially identical units wherein the additional units are stored for future transplants so that, if needed, the patient can receive a unit identical to one previously transplanted.
Alternatively, the additional like-units may be altered to optimize future transplants for that same patient.
In other embodiments, at least one type of cell is excluded from the cytotherapeutic omit comprising preselected potent cells. The cytotherapeutic unit is preferably certified as to its contents of the preselected potent cells and the absence of the types of cells to be excluded. In other embodiments, the identity and the numbers of a plurality of potent cells being selected to render the cytotherapeutic unit suitable for therapy for an indicated disease state or condition is certified. In some embodiments, the certification is preferably of a plurality of potent cell types, wherein the plurality aazd the numbers of each of said plurality being selected as well as excluded renders the cytotherapeutic unt suitable for therapy for an indicated disease state or condition.
In some embodiments, the present invention provides for kits for the treatment of a person suspected of having a disease state or condition. The lcit preferably comprises a cytotherapeutic unit comprising a plurality of potent cells. In some embodiments, the kit comprises a cytotherapeutic unit wherein at least one type of cell that has been excluded from the cytotherapeutic unit. In some preferred embodiments, the lcit comprises potent cells wherein at least some of the potent cells have been identified and counted. In some embodiments, the lcit comprises a unit that has been assayed to ensure the accuracy of the identities and numbers of the potent cells. In some more preferred embodiments of the kit, the accuracy of the assay has been certified.
The present invention provides kits for the treatment of a person suspected of having a disease state or condition comprising a cytotherapeutic unit having minimum numbers of identified potent cells and a certification of the potent cell composition.
The kits may also contain equipment or devices for administering the unit to the patient, materials for monitoring the administration and other attendant things.
In some embodiments, the present invention provides for cytotherapeutic wits comprising cells derived from umbilical cord blood, placenta, or a mixture thereof, wherein at least one type of cell has been removed from the unit. In some embodiments, a plurality of cell types has been removed from the unit.
The present invention provides for a cytotherapeutic unit comprising cells derived from umbilical cord blood, placenta, or a mixture thereof, wherein said cells comprise a plurality of different types. In some embodiments at least some of the different types of cells are separated into components. h1 other embodiments, the components are recombined into the unit. It is preferred in some aspects of the invention that components are used to supplement a cytotherapeutic unit with a specific potent cell type. The separated components can be frozen separately or otherwise stored prior to recombination. In some other embodiments, the cytotherapeutic unt itself has been placed in a frozen state. In some further embodiments, the separated cell types have.been identified and/or counted.
The present invention provides methods of treating a disease in a mammal comprising administering to the mammal a therapeutically effective amount of a composition comprising a cytotherapeutic unit. The uut used to treat the disease state or condition comprises a plurality of potent cells wherein the content of the unit is lenown with respect to the identities and numbers. At least some of the cells in the unit are assayed to ensure the accuracy of the identities and the numbers of the potent cells. In some preferred embodiments, the cytotherapeutic unit is administered multiple times. In other cases, administering multiple doses of the cytotherapeutic uW is that are derived from different individuals or sources may be performed.
The methods may also comprise administering multiples doses of the cytotherapeutic unit that is derived from one individual.
The present invention provides for cytotherapeutic units comprising a plurality of potent cells with the content of the cytotherapeutic unit being l~nown with respect to the identities and numbers of at least some of the potent cells.
The identities of the potent cells in the cytotherapeutic unit are an aspect of the invention that is important for the reliability and the quality of the unit being used. The potent cells can be identified by any number of methods and based on any set of criteria that a person of ordinary shill may find useful. One such method is to identify the potent cells based on the presence of antigenic determinants on the surface of the cell. Antigenic determinants can be any molecule that is recognizable by an antibody. Some examples of antigenic determinants include polypeptides, lipids, glycoproteins, sugars, and the life. Additionally, the cells may be characterized by the presence of one or more of the following cell surface markers:
CD10+, CD29+, CD34-, CD3~-, CD44+, CD45-, CD54+, CD90+, SH2+, SH3+, SH4+, SSEA3-, SSEA4-, OCT-4+, and ABC-p+.
Although some potent cells may be identified by the presence of antigenic determinants or by certain expressed factors, it can be equally important to identify a cell based on what antigenic determinants the cell lacks. For example, it is known that the presence of certain determinants may lower the chances of a successful treatment and therefore, a person using the cytotherapeutic unit would want to know that the unit being used lacks certain antigenic determinants. Furthermore, the presence or absence of antigenic factors can aid in determining the maturity level of a particular cell or cell-type. A less mature cell has a wider range of differentiation and is therefore, potentially more useful. Depending on the use of the cytotherapeutic unit, different levels of differentiation of the cells may be required. The identification of some of the cells enables a person to obtain a unit, that when used, results in a better clinical outcome.
Methods to determine the presence or absence of antigeuc factors on or in a cell are well known in the art. These methods include fluorescence activated cell sorting (FACS), Enzyme-Linked Immuno Sorbent Assay (ELISA), western blot, polymerase chain reaction (PCR), reverse-transcribed PCR (RT-PCR), and the life.
The precise method or methods used to identify the potent cells is not essential.
Other criteria to identify a cell can be based on the genetic makeup of the cell.
Genes play an essential role in everything that occurs in a cell. Because of this fact, a person of ordinary skill in the art may identify a potent cell based on its genes. More specifically, a person of ordinary shill in the art may identify a cell based on the genes that are wild-type, mutant, being expressed, not being expressed, contain polymorphisms, or a combination thereof. As used herein, the term "expressed"
means whether or not the gene is being transcribed into RNA or whether a protein is ultimately produced by that gene.
The methods to determine the genetic profile of a cell axe well known to those of ordinary skill in the art. Any method used is sufficient, but some examples of methods or techniques that can be used to determine the genetic makeup of a cell include, without limitation, PCR, RT-PCR, northern blot, southern blot, single nucleotide polymorphism (SNP) analysis, gene-chip expression analysis, serial analysis of gene expression (SAGE), nucleotide sequencing, FAGS, ih situ hybridization, and the lilce.
In some embodiments of the present invention, a cell can be identified by any of the above-mentioned criteria: antigenic determinants, genetic makeup, a combination thereof, or a cell can be identified based upon another set of criteria. h1 some embodiments, at least 0.1%, 1%, at least 10 %, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80 %, at least 90%, at least 95%, or about 100% of the cells are identified.
Methods of identification and determining the number of cells are well l~nown in the art , they include but are not limited to using standard cell detection techniques such as flow cytometry, cell sorting, immunocytochemistry (e.g., staining with tissue specific or cell-marker specific antibodies), FAGS, magnetic activated cell sorting (MACS), by examination of the morphology of cells using light or confocal microscopy, or by measuring changes in gene expression using techniques well known in the art, such as PCR and gene expression profiling. Additionally, relevant determinations can be made by techniques including, but not limited to, optical and electrooptical properties, morphological imaging methods, optophoresis (www.genoptix.com) microwave spectroscopy (Signature Bioscience www.signaturebio.com) and optical tweezers. Other methods may also be employed.
It is known that specific cell-types or cells having particular antigenic determinants can have a deleterious effect on the success rate of cytotherapy.
Therefore, the present invention provides for cytotherapeutic units that have at least one cell type that is excluded. The cell-type that is excluded will not always be the same. In some embodiments, all CD34 positive cells will be excluded. In some other embodiments all CDS positive cells will be excluded. In some other embodiments multiple cell types are excluded. In some applications, it may be acceptable and convenient to reduce, rather than eliminate, selected cell types to improve therapeutic success. Thus, the term "exclusion" or "elimination" as used in this context preferably means at least about 75% reduction in the number of a certain cell type in a cell preparation. Preferably, at least about 90% reduction is achieved, with at least about 95% reduction being even more preferred. Essentially complete elimination is, of course, most desirable, although the same may be achievable in some cases. The foregoing percentage reductions relate to numbers of cells relative to an original population of such cells using any appropriate assay.
Cell types can be excluded or reduced either by selecting cell-containing units which, naturally do not contain them (or many of them) or by employing a process that specifically removes selected cell-types. It is preferred to exclude cell types having antigenic determinants which are inconsistent with the therapeutic modality planned for the cytotherapeutic unit. For example, but not by way of limitation, T-lymphocytes and mature dendritic cells may be excluded to lower the expectation of to graft versus host disease. In the treatment of adrenal leukodysplasia it may be desirable to delete some or all CD8 positive cells.
To be excluded "naturally" means that the preparation of cells that is derived from a source does not contain a specific cell type without further manipulation or contains a very small population of such types. Alternatively, a cell-type can be excluded by a process that is used either before or after the cells are extracted from a source. Processes or methods that are used to exclude a specific cell-type are well known to the art-skilled. Examples of processes or methods include: FACS, centrifugation, immunochromatography, and the like.
In one embodiment, the cells may be sorted using a fluorescence activated cell sorter (FACS). Fluorescence activated cell sorting (FACS) is a well-lcnown method for separating particles, including cells, based on the fluorescent properties of the particles (Kamrach, 1987, Methods Enzymol, 151:150-165). Laser excitation of fluorescent moieties in the individual particles results in a small electrical charge allowing electromagnetic separation of positive and negative particles from a mixture.
In one embodiment, cell surface marker-specific antibodies or ligands are labeled with distinct fluorescent labels. Cells are processed through the cell sorter, allowing separation of cells based on their ability to bind to the antibodies used.
FAGS sorter particles may be directly deposited into individual wells of 96-well or 384-well plates to facilitate separation and cloning. Reagents for cell surface markers or cluster designated reagents are available from a variety of sources including Becton Dickinson and Cell Pro Inc., for example.
Available reagents include but are not limited to reagents for identifying:
CDla; CD2; CD3; CD4; CD4 (Multi-Clone); CD4 v4; CDS; CD7; CD8 (Leu-2a); CD8 (Leu-2b); CD10 (Anti-CALLA); CDlla (Anti-LFA-la); CDllb;
CDllc; CD13; CD14; CD15; CD16 (Leu-lla, 11b, llc); CD18 (Anti-LFA-1(3);
CD19 (Leu-12); CD19(SJ25C1); CD20; CD21(Anti-CRZ); CD22; CD23;
CD25(Anti-IL-2R); CD26; CD27; CD28; CD31(Anti-PECAM-1); CD33;
CD34(Anti-HPCA-1&2); CD38; CD42a(Anti-gpIX); CD44; CD45(Anti-Hle-1);
CD45RA; CD45R0; CD49d(Anti-VLA-a4); CD54; CD56(MY31);
CD56(NCAM16.2); CD57; CD58(Anti-LFA-3); CD61; CD62P; CD62L(Leu-8);
CD69; CD71; CD80(Anti-BB1B7); CD95; CD117; CD122(Anti-IL-2Rp75);
CD123(Anti-IL-3Ra); CD134(Ox40); CD154(CD40L); CD158a; CD161; Lineage Cocktail 1 (linl) FITC and others now known or hereafter discovered.
Non-cluster designated reagents include: Anti-BrdU; Anti-Cytokeratin (CAM
5.2); Anti-HER-2/neu; Anti-HLA-DP; Anti-HLA-DQ; Anti-HLA-DR; Anti-Hu KIR (NKB1); Anti-IgA2; Anti-IgD; Anti-IgG; Anti-IgM (Ig Heavy Chain); Anti-Kappa (Ig Light Chain); Anti-Kappa F(ab')2; Anti-Lambda (Ig Light Chain); Anti-Lambda F(ab')2; Anti-P-glycoprotein (P-gp); Anti-TCR a/(3-1 (WT31); Anti-TCR-y/8-1; PAC-1; Lineage Coclctail 1 (linl) FITC. The skilled artisan will use those reagents required for his/her particular needs in order to optimize the desired cytotherapeutic unit or tailor it for a particular patient or use.
In another embodiment, magnetic beads can be used to separate cells. The cells may be sorted using a magnetic activated cell sorting (MACS) technique, a method for separating particles based on their ability to bind magnetic beads (0.5-100~,m diameter). A variety of useful modifications can be performed on the magnetic microspheres, including the covalent addition of an antibody which specifically recognizes a cell-solid phase surface molecule or hapten. A
magnetic field is then applied, to physically manipulate the selected beads. The beads are then mixed with the cells to allow binding. Cells are then passed through a magnetic field to separate out cells having cell surface markers. These cells can then isolated and re-mixed with magnetic beads coupled to an antibody against additional cell surface markers. The cells are again passed through a magnetic field, isolating cells that bound both the antibodies. Such cells can then be diluted into separate dishes, such as microtiter dishes for clonal isolation, if desired.
Knowing the composition of the cytotherapeutic unit will help fulfill the long-felt need of a reliable and certified cytotherapeutic unit. In addition to the composition of the unit, it can be useful to know the numbers of at least some of the cells in the cytotherapeutic unit. In some embodiments, just the numbers of cells will be known without lrnowing the specific identity of any of the cells. In some other embodiments, the numbers of cells will be known, but also the numbers of the identified cells will be lcnown. To determine the number of cells in total is well known to those of ordinary skill in the art. Examples of equipment that can be used to count cells are a machine that performs FACS or flow cytometry, or a much simpler piece of equipment, a hemacytometer. Often the number of the cells will be determined at the same time the identities are determined, but the numbers can also be determined before or after the identities of some of the potent cells are determined.
By knowing the number of the cells present in a cytotherapeutic unit this will give a person using the unit the lcnowledge of what is being administered, something that is sorely lacking in present cytotherapies.
The knowledge of the numbers of total cells and also the numbers of specific cell types in a cytotherapeutic unit can be used to supplement the unit with additional cells or cell types so that a minimum number of cells or a minimum number of a specific cell type can be present in the unit. It is thought that the diverse responses seen in cytotherapy is in part due to the varying number of cells recovered from a source using the cellular preparation techniques in use today.
By identifying and counting the cells this will allow a more thorough analysis of what is required for a successful treatment as well as the ability to perform a thorough and complete analysis on the importance of a specific cell type in a cellular preparation.
Cytotherapeutic units can now be prepared that have a minimum numbers of preselected cells. It is also now possible to ensure that other cell types are excluded from the units. In some embodiments the cytotherapeutic unit will comprise at least about 100 selected potent cells. Such units having at least about 1,000 such cells are preferred, with at least about 10,000 being more preferred. Greater numbers of selected cells are still more preferred, especially when it is intended that the unit be administered to the same or different individuals a plurality of times. Thus, selected cell populations greater than about 100,000 or even about 500,000 can be useful. It is preferred that some or all of the cells in the unit be identified through assay and that the same be reflected in a certification of such presence. This certification ensures uniform and effective therapeutic application.
In some embodiments of the present invention, the cytotherapeutic units will have a minimum number of different, specific cell types. Advantages to having a minimum number of specific cell types are that it may improve the efficacy of the cytotherapeutic unit. For example, the cytotherapeutic unit could be assayed to comprise at least about 1,000 OCT4 positive cells, either with or without lrnown quantities of other desirable cell types. In other embodiments, the unit may be caused to comprise specific percentages of CD34 positive cells, measured by reference to all nucleated cells in the preparation. Thus, such preparations may contain at least 0.01%, 0.1%, 1%, 10%, 20%, 30%, 40%, 50%, 60%, 70 %, 80%, 90%, 95% or other percentages of CD34 positive cells may be made. Similar, known percentages of cells having other antigenic determinants or specific factors may, lilcewise, be created.
Other embodiments of the present invention provide for cytotherapeutic omits comprising cells that have been derived from at least one source, wherein the source's cells have been separated into components. As used herein, the term "components" is synonymous to cell-types, identified cells, and the lilce. Methods to separate cellular preparations into components that are well known to those of skill in the art include, without limitation, FACS, centrifugation, chromatography, HPLC, FPLC, and the like.
Thus, cytotherapeutic uiuts can comprise components that axe recombined. In some embodiments, at least one component is used in a cytotherapeutic unit. In some other embodiments, at least two, at least three, at least 4, at least S, at least 10, at least 100 components are recombined to make the cytotherapeutic unit. It is preferred that the components of each source be known in terms of identity and relative numbers, with some cell types preferably being excluded from some or all of the components.
It may be seen that the different components may be maintained separately, e.g.
frozen, and that the same may form a "formulary" or "library" of cells of known identity and abundance for formulation into combined cytotherapeutic units.
Separating the respective cellular preparations into components allows a cytotherapeutic unit to be created that has a specific composition both in terms of cells present and in types of cells excluded. Additionally, this allows an existing cytotherapeutic unit to be supplemented with a specific cell-type or component as may be indicated for a specific therapeutic modality.
Thus, cytotherapeutic units"of the invention may be seen to comprise cells derived from one source or from many sources. Contrary to prevailing practice, it is believed that there are great benefits to providing cells from a plurality of sources and that therapeutic benefit and efficacy will derive therefrom. In some embodiments, the cells are derived from multiple sources and may derive from multiple organs in such sources. As used herein, the term "source" refers to any organism, tissue, or organ from which cells are derived or extracted. In some embodiments, the sources are fetal cord blood, fetal tissue, placenta, postpartum placenta, postpartum placenta perfusate, or a mixture thereof. It is well known to those of ordinary skill how to extract cells from different tissues or organs. Methods to extract cells from fetal cord blood can be -found in, for example in U.S. Patent No. 5,372,581, entitled "Method and apparatus for placental blood collection," issued December 13, 1994; Hessel et al., U.S.
Patent No. 5,415,665, entitled "Umbilical cord clamping, cutting, and blood collecting device and method", issued May 16, 1995. The needle or cannula is usually placed in the umbilical vein and the placenta is gently massaged to aid in draining cord blood from the placenta. Methods to extract cells from placenta, post-partum placenta, or post-partum placenta perfusate can be found in, for example, International Patent Publications WO 02/46373 and WO 02/064755, each of which are herein incorporated by reference in their entireties.
In another embodiment, the cells are stimulated to proliferate, for example, by administration of erythropoietin, cytoleines, lympholcines, interferons, colony stimulating factors (CSF's), interferons, chemolcines, interleukins, recombinant human hematopoietic growth factors including ligands, stem cell factors, thrombopoeitin (TPO), interleulcins, and granulocyte colony-stimulating factor (G-CSF) or other growth factors.
In another embodiment; cells are genetically engineered, for example, using a viral vector such as an adenoviral or retroviral vector, or by using mechanical means such as liposomal or chemical mediated uptake of the DNA.
A vector containing a transgene can be introduced into a cell of interest by methods well lcnown in the art, e.g:, transfection, transformation, transduction, electroporation, infection, microinjection, cell fusion, DEAF extran, calcium phosphate precipitation, liposomes, LIPOFECTINTM, lysosome fusion, synthetic cationic lipids, use of a gene gun or a DNA vector transporter, such that the tra~isgene is transmitted to daughter cells, e.g., the daughter embryonic-like stem cells or progenitor cells produced by the division of an embryonic-like stem cell. For various techniques for transformation or transfection of mammalian cells, see Keown et al., 1990, Methods Enzymol. 185:527-37; Sambrook et al., 2001, Molecular Cloning, A
Laboratory Manual, Third Edition, Cold Spring Harbor Laboratory Press, N.Y.
The cytotherapeutic units will preferably comprise minimum numbers of preselected types of potent cells and be certified as such. As used herein, "preselected" refers to the process of selecting the types of potent cells that are to be in the cytotherapeutic unit before it is administered. Preselecting the types of potent cells that will have a minimum number of those cells in the cytotherapeutic unit allows the cytotherapeutic unit to be tailored to a composition desired to achieve a specific therapeutic result in an individual or class of individuals.
Likewise, certification as to the absence of other preselected types of cells is preferred for similar reasons.
The plurality of potent cells and of cell types present in the cytotherapeutic units of the invention are selected to render the units suitable for therapy for an indicated disease state or condition. As used herein, the phrase "selected to render"
refers to the process of deciding that a cytotherapeutic unit comprising a plurality of potent cells is suitable for therapy. This decision can be based on the numbers of potent cells present in the cytotherapeutic unit. As discussed hereinbefore, the number of cells appears to be critical for the success rate of treating an individual or patient with cytotherapy. Therefore, not all cytotherapeutic units may be suitable for therapy for an indicated disease state or condition. Additionally, the types of potent cells will also aid in the decision process on whether or not a cytotherapeutic unit is suitable for therapy. Certain types of potent cells card be detrimental or beneficial to the treatment of a specific disease state or condition. Thus, the types of cells present in the unit can be another factor that is used to select a unit suitable for therapy. The criteria that are used to select a unit that is suitable for therapy is not specific to those mentioned above. Any set of criteria can be used to decide whether or not a plurality of potent cells present in a cytotherapeutic unit are selected to render the unit suitable for therapy of an indicated disease state or condition.
The present invention provides for cytotherapeutic units wherein at least some of the potent cells present in the unt are identified and counted. However, for the units to be relied upon in scientific;research and to be used as a cytotherapeutic the units' contents must be preferably assayed to ensure the accuracy of the identities and numbers. The assays can be done by the same group, individual, or machine that had determined the identities and the numbers of at least some of the potent cells in the cytotherapeutic units. However, the assays can be performed by a different individual, group, or machine that had determined the identities and numbers of some of the potent cells. In some embodiments, only one assay needs to be performed to ensure the accuracy of the identities and the numbers. In some other embodiments, at least 2, at least 5, or at least 10 assays are performed to ensure the accuracy of the identities and the numbers of the potent cells. The types of assays to be done can be the same assay that was used to determine the numbers and the identities previously.
In some other embodiments, different assays are used to ensure the accuracy of the numbers and identities of some of the potent cells. Some assays that can be used to ensure the accuracy include, without limitation, ELISA, FAGS, western blot, and the like.
In some other embodiments, the provider of the unit certifies the accuracy of the assay. As used herein, the term "provider" refers to an individual, business, or facility that is providing the cytotherapeutic unit to the individual that is using the unit. In some embodiments, the certification comprises a m.-itten statement indicating that the assay was performed correctly and that the results are correct. In some other embodiments, the certification comprises results from an assay done on a positive control to show that the assay was functioning properly. In some other embodiments, the certification comprises both the results of the positive control and a written statement that the assay was functioning properly. In some further embodiments, the certification comprises a list of the types of potent cells that have been excluded from the cytotherapeutic unit. In some further embodiments, the certification comprises a list of at least some of the types of potent cells that are contained in the cytotherapeutic u~zit. In some embodiments, the certification comprises the numbers of all the cells. In some embodiments, the certification further comprises the quantity of at least some of the specific cell types. W some other embodiments, the certification comprises a list of the types of at least some of the potent cells that have been added to the unit to supplement the potent cells so that the unit comprises minimum numbers of potent cells.
The present invention also provides for bits for the treatment of a person suspected of having a disease state or condition comprising a cytotherapeutic unit comprising a plurality of potent cells with the content of the unit being known with respect to the identities and numbers of at least some of the potent cells.
Additionally, the cytotherapeutic unit is assayed to ensure the accuracy of the identities and numbers of the potent cells. The lcits further comprise a certification of the accuracy of the assay. In some embodiments, the bits comprise a cytotherapeutic unit having minimum numbers of identified potent cells and a certification of the potent cell composition of the unit. In some other embodiments, the kits comprise cytotherapeutic units that have at least one cell-type that has been excluded.
The present invention also provides for methods of treating a disease state or condition in a mammal. The methods comprise administering to the mammal a therapeutically effective amount of a composition comprising a cytotherapeutic unit comprising potent cells, wherein some of the potent cells are known with respect to their identities and numbers. The unit is also assayed to ensure the accuracy of the identities and the numbers. In some other embodiments, the cytotherapeutic unit comprises minimum numbers of preselected types of potent cells.
A therapeutically effective amount for a mammal can vary, but for example could be approximately 0.01 cytotherapeutic muts/lcg to 100 units/lcg. The cytotherapeutic unit can be administered rapidly or slowly to the mammal. In some embodiments, the cytotherapeutic unit is administered at a rate of approximately 0.01 ~,l /minute, and in other embodiments, the unit is administered at a rate of approximately 100,000 ml/minute. The unit can be administered, for example, intravenously, subcutaneously, intramuscularly, orally, or rectally. In some embodiments, the unit is administered multiple times to the mammal at different times. In some other embodiments, cytotherapeutic units derived from different sources or different individuals are administered to the mammal.
The potential uses for cytotherapeutic units are limitless, but some examples of disease states or conditions that cytotherapeutic units can be used to treat include cancer, acute leul~emia, chronic leul~emia as well as other cancers presently treated with bone marrow or cord blood cell transplants, myelodysplastic syndrome, stem cell disorder, myeloproliferative disorder, lymphoproliferative disorder, phagocyte disorder, liposomal storage disorder, histiocytic disorder, inherited erythrocyte abnormality, congenital (inherited) immune system disorder, inherited platelet abnormality, plasma cell disorder, Lesch-Nyhan Syndrome, Cartilage-Hair Hypoplasia, Glanzmann Thrombastenia, osteoporosis, breast caaicer, Ewing Sarcoma, neuroblastoma, renal cell carcinoma, lung cancer, Alzheimer's disease, liver disease, hepatitis, Parl~inson's disease, vision loss, memory loss, and the life.
The cytotherapeutic units may be optimized for enzyme replacement therapy to treat specific diseases or conditions, including, but not limited to, lysosomal storage diseases, such as Tay-Sachs, Niemann-Picl~, Fabry's, Gaucher's, Hunter's, and Hurler's syndromes, as well as other gangliosidoses, mucopolysaccharidoses, and glycogenoses. The cytotherapeutic units in this case may be certified that the cells have been assayed to contain the desired number of cells capable of producing the necessary enzyme. Said unit may contain either allogeneic cells containing the functional endogenous gene of the desired enzyme, autologous cells containing exogenous copies of the desired gene or a combination of both.
In other embodiments, the cells may be used as autologous or heterologous transgene caxriers in gene therapy to correct inborn errors of metabolism such as adrenoleul~odystrophy, cystic fibrosis, glycogen storage disease, hypothyroidism, sicple cell anemia, Pearson syndrome, Pompe's disease, phenyllcetonuria (PKI~, Tay-Sachs disease, porphyrias, maple syrup urine disease, homocystinuria, mucopolypsaccharidoses, chronic granulomatous disease, and tyrosinemia or to treat cancer, tumors or other pathological conditions.
The citation of any publication is for its disclosure prior to the filing date and should not be construed as an aclinission that present invention is not entitled to antedate such publication by virtue of prior invention.
The present invention is not to be limited in scope by the specific embodiments described herein. hideed, various modifications of the invention in addition to those described herein will become apparent to those spilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.
All references cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety for;all purposes.
An adult having acute myelogenous leukemia (AML) is in need of hematopoetic reconstitution by way of a cell transplant. The patient undergoes traditional chemotherapy followed by conventional preparation for tra~zsplant as determined by the patient's health care provider but includes destroying the diseased bone marrow. The patient's weight is determined. Appropriate HLA typing has been done by conventional methods. Based on these parameters, which include the disease to be treated, the patient's body weight and HLA matching, the transplanter requests and is provided with a cytotherapeutic unit comprising a plurality of potent nucleated cells; the content of said mlit being l~nown with respect to the identities and numbers at least some of said plurality; the unit being assayed to ensure the accuracy of said identities and numbers, which is certified. In particular, the unit is certified to contain about 1.4 x 10~ nucleated cells per l~ilogram of the patient's body weight.
Additional certified information includes HLA information. Because the patient suffers from AML, the cytotherapeutic unit contains no less than one (1) percent of CD34+
of the total nucleated cells and no less than 2.5 percent CD8+ cells to minimize graft versus tumor effect. In this case the transplanter requests twice the total number of cells needed for transplant (1.4 x 10' nucleated cells multiplied by the patient's weight in ltilograms x2). The transplanter requests the lx amount just prior to the transplant in order to have the number of cells suitable for this transplant. The second half of the cells is to be shipped in the event that a second transplant becomes necessary.
Accordingly, the second cytotherapeutic unit is the same as that to be used in the initial transplant. Alternatively, the transplanter may request, based on alterations in the patient's weight, severity of disease or even changes in recommended treatment, that the second cytotherapeutic unit be altered in the appropriate mamler (increased number of CD34 positive cells, etc.) and certified. The transplant is performed in the same mamzer conventionally used by the transplanter.
A child having siclcle cell anemia is in need of a cell transplant. It is determined that 1.7 x 10' nucleated cells per l~ilogram of body weight of the child is needed. Appropriate HLA typing is done by conventional methods. It is determined that the cytotherapeutic unit must have no less than 1% CD34+ cells of the total nucleated cells. Said CD34+ cells are further described in a ratio of 2:1 as CD34+/CD33+: CD34+/CD33- A cytotherapeutic unit having these parameters is provided. This unit comprises cells derived from cord blood as well as pluripotential placental cells such as those described in WO 02/064755, which are derived in the manner described in W002/064755. The ratio of CD34+/ CD33+
cells is 2:1 to CD34+/ CD33-, a fact which is ascertained by assay and certified as being accurate. The certified cells are determined using FACS; based on the fluorescent properties of the particles, cell surface marker-specific antibodies or ligands are labeled with distinct fluorescent labels. Cells are processed through the cell sorter, allowing separation of cells based on their ability to bind to the antibodies used. Cell surface marker-specific antibodies may be purchased from any company selling such reagents, including Becton Dickinson, for example. The transplant is performed in the same manner conventionally used by the transplanter.
A child suffers from adrenal leukodysplasia. It is determined that a cellular transplant is appropriate. It is determined that 2 x 10' nucleated cells (derived from cord blood by a conventional technique) per kilogram of body weight of the child is needed. Appropriate HLA typing is done by conventional methods. A
cytotherapeutic unit having these parameters is provided. In particular, the unit is certified to contain no less than 0.25% of CD34+/ CD38- cells and with no less than 0.5% depletion of CD8+ cells of the total nucleated cells. The transplant is performed in the same manner conventionally used by the transplanter.
AND METHODS FOR TREATMENTS USING THEM
FIELD OF THE INVENTION
The present invention is directed to improvements in therapeutics utilizing cytotherapeutic formulations. Cytotherapeutic therapy involves the introduction of immature cells, especially stem cells, into a patient in order to secure palliation, amelioration or cure of a disease state. The present invention is also directed to improved cytotherapeutic agents, to methods of producing them, to unit dosage forms of such agents and to novel paradigms for administering cytotherapeutic units to patients in need of therapy.
BACKGROUND OF THE INVENTION
It has been known heretofore to administer certain types of stem cells to humans and to animals in order to achieve a therapeutic end. Much of this has been done with stem cells from adults, such as those found in adult bone marrow, especially for the repopulation of depopulated interosseous spaces, which attend aggressive chemotherapy or radiation therapy, e.g., for treatment of certain cancers.
Indeed, such cytotherapy has become relatively widespread and has achieved a level of success despite limitations including the lacy of standardization as to cell numbers and types.
Many of these therapeutic regimes employ relatively mature cellular preparations, e.g. bone marrow. While these have a level of therapeutic potential, such cells possess quite a large number of surface antigens and require imrnunosupression attendant to administration. Additionally, most cells extracted from adult bone marrow are limited in the types of cells into which they can differentiate. There have been a number of reports that have indicated that most stem cells isolated from adult bone marrow are only able to differentiate into blood cells.
While this is useful for the treatment of blood related diseases, e.g., leukemia, these cells are not very useful for treating other types of diseases that are localized to a specific type of tissue or organ. An additional problem with bone marrow preparations is that the process of extracting the marrow is often very painful, and although potential donors can be identified many do not consent to the procedure because of the potential for pain and discomfort.
Recently, cytotherapy employing less mature stem cells, such as, for example, those found in neonatal cord blood, has found some success. However, stem cell preparations from most sources, including from neonatal cord blood, include a diverse population of cells with differing potentials for effective therapy and often do not contain a sufficient number of cells for an optimized therapeutic dose, particularly for an averaged size adult undergoing a transplant for leukemia, for example. It is believed that different scientific and medical groups likely achieve differing preparations with differing characteristics, even when supposedly following the same or similar protocols. Presently, most independent preparations, even those done by the same individual, can have different compositions with the specifics of the compositions undetermined. In short, there is a complete laclc of unit to unit reproducibility and little standardization in the cellular units used in transplants.
The foregoing practices can give rise to inconsistent therapeutic outcomes from different research and medical centers and make accurate, statistical analyses for cytotherapeutic procedures difficult or impossible to attain. There is, thus, a long-felt need for improved cytotherapeutic materials and procedures, ones amenable to reproducible outcomes and to scientific analysis. It is also desired to improve specificity of cytotherapeutic treatments and to affect improved efficiencies and outcomes. Importantly, there is also a need for unit to uut reproducibility which may further the ability to collect sufficient data to advance the medical area devoted to cellular therapies. The present invention provides solutions for these and other long-felt needs.
SiJMMARY OF THE INVENTION
As used herein, "cytotherapeutic unit" refers to a cell preparation comprising a plurality of potent cells in which at least one cell type has been tailored for a particular patient or particular disease state. Tailoring may include having a minimum number of said cell type or, alternatively, removal of a portion or all of said cell type.
"Potent," with respect to a cell or cell type, means that the cell or cell type is capable of differentiation into at least one type of cell.
"Pluripotent," with respect to a cell or cell type, means that the cell or cell type is capable of differentiation into at least two different types-of cells.
"Antigenic determinant" refers to the set of antigenic regions on the surface of a cell.
"Factor" refers to a cell type by reference to its antigenic determinant.
Exemplary factors include CD34, CDB, CD10 and the lilce. A cell or cell preparation may also be considered to be positive or negative in regard to a particular factor by reference to whether or not a particular cell or cell type exhibits the characteristics of that particular factor.
The present invention provides for cytotherapeutic units comprising a plurality of potent cells, the contents of which are l~nown with respect to the identities and numbers of at least some of the potent cells. To ensure that the identities and numbers of at least some of the potent cells are accurate at least one assay is performed. In some preferred embodiments, the provider of the unit certifies the accuracy of the assay. In other embodiments, the potent cells for wluch the identities and numbers are known are pluripotent cells. The identities of the potent cells preferably reflect the presence or absence of at least one antigenic determinant on the cells. In some embodiments, the cytotherapeutic unit comprises at least some potent cells exhibiting CD34, CDB, CD10, OCT4, CD38, CXCR4, or CD117, for example. In some embodiments some portion of the cells may also exhibit CD33. In some preferred embodiments, the cytotherapeutic trait comprises cells that lack specific antigenic determinants. In other embodiments, at least one identified potent cell that is derived from a source is specifically excluded or removed from the cellular preparation.
In one embodiment of the invention, some or all cells may be characterized by the presence of one or more of the following cell surface markers: CD10+, CD29+, CD34-, CD38-, CD44+, CD45-, CD54+, CD90+, SH2+, SH3+, SH4+, SSEA3-, SSEA4-, OCT-4+, and ABC-p+.
The potent cells may be obtained from fetal cord blood or other fetal tissue.
In some embodiments, potent cells are obtained from placenta, especially postpartum placenta, which has been metabolically supported and nurtured. Potent cells are preferably obtained from postpartum placenta perfusate. The present invention also provides for cytotherapeutic units wherein the potent cells are derived from a plurality of sources. In some embodiments, the potent cells are derived from at least two individuals, at least five individuals, or at least ten individuals. In some embodiments, the unit comprises at least one cell that is autologous. In some other embodiments, the unit comprises at least one cell that is exogenous. In some embodiments the unit comprises a chimera of autologous and allogeneic cells.
In another embodiment at least some of the cells are genetically modified.
In other embodiments, the plurality of potent cells is selected to render the unit suitable for therapy for an indicated disease state or condition and/or the severity of the condition. In some preferred embodiments, the cytotherapeutic units comprise a minimum number of preselected types of potent cells and may be based, for example, on the weight of the particular patient or that patient's medical status. In some prefeiTed embodiments, the cytotherapeutic unit is assayed to ensure the accuracy of its contents of preselected types of potent cells. In some preferred embodiments, the contents of the preselected potent cells in the cytotherapeutic unit are certified. In other embodiments, the cytotherapeutic unit can be one of a group of substantially identical units wherein the additional units are stored for future transplants so that, if needed, the patient can receive a unit identical to one previously transplanted.
Alternatively, the additional like-units may be altered to optimize future transplants for that same patient.
In other embodiments, at least one type of cell is excluded from the cytotherapeutic omit comprising preselected potent cells. The cytotherapeutic unit is preferably certified as to its contents of the preselected potent cells and the absence of the types of cells to be excluded. In other embodiments, the identity and the numbers of a plurality of potent cells being selected to render the cytotherapeutic unit suitable for therapy for an indicated disease state or condition is certified. In some embodiments, the certification is preferably of a plurality of potent cell types, wherein the plurality aazd the numbers of each of said plurality being selected as well as excluded renders the cytotherapeutic unt suitable for therapy for an indicated disease state or condition.
In some embodiments, the present invention provides for kits for the treatment of a person suspected of having a disease state or condition. The lcit preferably comprises a cytotherapeutic unit comprising a plurality of potent cells. In some embodiments, the kit comprises a cytotherapeutic unit wherein at least one type of cell that has been excluded from the cytotherapeutic unit. In some preferred embodiments, the lcit comprises potent cells wherein at least some of the potent cells have been identified and counted. In some embodiments, the lcit comprises a unit that has been assayed to ensure the accuracy of the identities and numbers of the potent cells. In some more preferred embodiments of the kit, the accuracy of the assay has been certified.
The present invention provides kits for the treatment of a person suspected of having a disease state or condition comprising a cytotherapeutic unit having minimum numbers of identified potent cells and a certification of the potent cell composition.
The kits may also contain equipment or devices for administering the unit to the patient, materials for monitoring the administration and other attendant things.
In some embodiments, the present invention provides for cytotherapeutic wits comprising cells derived from umbilical cord blood, placenta, or a mixture thereof, wherein at least one type of cell has been removed from the unit. In some embodiments, a plurality of cell types has been removed from the unit.
The present invention provides for a cytotherapeutic unit comprising cells derived from umbilical cord blood, placenta, or a mixture thereof, wherein said cells comprise a plurality of different types. In some embodiments at least some of the different types of cells are separated into components. h1 other embodiments, the components are recombined into the unit. It is preferred in some aspects of the invention that components are used to supplement a cytotherapeutic unit with a specific potent cell type. The separated components can be frozen separately or otherwise stored prior to recombination. In some other embodiments, the cytotherapeutic unt itself has been placed in a frozen state. In some further embodiments, the separated cell types have.been identified and/or counted.
The present invention provides methods of treating a disease in a mammal comprising administering to the mammal a therapeutically effective amount of a composition comprising a cytotherapeutic unit. The uut used to treat the disease state or condition comprises a plurality of potent cells wherein the content of the unit is lenown with respect to the identities and numbers. At least some of the cells in the unit are assayed to ensure the accuracy of the identities and the numbers of the potent cells. In some preferred embodiments, the cytotherapeutic unit is administered multiple times. In other cases, administering multiple doses of the cytotherapeutic uW is that are derived from different individuals or sources may be performed.
The methods may also comprise administering multiples doses of the cytotherapeutic unit that is derived from one individual.
The present invention provides for cytotherapeutic units comprising a plurality of potent cells with the content of the cytotherapeutic unit being l~nown with respect to the identities and numbers of at least some of the potent cells.
The identities of the potent cells in the cytotherapeutic unit are an aspect of the invention that is important for the reliability and the quality of the unit being used. The potent cells can be identified by any number of methods and based on any set of criteria that a person of ordinary shill may find useful. One such method is to identify the potent cells based on the presence of antigenic determinants on the surface of the cell. Antigenic determinants can be any molecule that is recognizable by an antibody. Some examples of antigenic determinants include polypeptides, lipids, glycoproteins, sugars, and the life. Additionally, the cells may be characterized by the presence of one or more of the following cell surface markers:
CD10+, CD29+, CD34-, CD3~-, CD44+, CD45-, CD54+, CD90+, SH2+, SH3+, SH4+, SSEA3-, SSEA4-, OCT-4+, and ABC-p+.
Although some potent cells may be identified by the presence of antigenic determinants or by certain expressed factors, it can be equally important to identify a cell based on what antigenic determinants the cell lacks. For example, it is known that the presence of certain determinants may lower the chances of a successful treatment and therefore, a person using the cytotherapeutic unit would want to know that the unit being used lacks certain antigenic determinants. Furthermore, the presence or absence of antigenic factors can aid in determining the maturity level of a particular cell or cell-type. A less mature cell has a wider range of differentiation and is therefore, potentially more useful. Depending on the use of the cytotherapeutic unit, different levels of differentiation of the cells may be required. The identification of some of the cells enables a person to obtain a unit, that when used, results in a better clinical outcome.
Methods to determine the presence or absence of antigeuc factors on or in a cell are well known in the art. These methods include fluorescence activated cell sorting (FACS), Enzyme-Linked Immuno Sorbent Assay (ELISA), western blot, polymerase chain reaction (PCR), reverse-transcribed PCR (RT-PCR), and the life.
The precise method or methods used to identify the potent cells is not essential.
Other criteria to identify a cell can be based on the genetic makeup of the cell.
Genes play an essential role in everything that occurs in a cell. Because of this fact, a person of ordinary skill in the art may identify a potent cell based on its genes. More specifically, a person of ordinary shill in the art may identify a cell based on the genes that are wild-type, mutant, being expressed, not being expressed, contain polymorphisms, or a combination thereof. As used herein, the term "expressed"
means whether or not the gene is being transcribed into RNA or whether a protein is ultimately produced by that gene.
The methods to determine the genetic profile of a cell axe well known to those of ordinary skill in the art. Any method used is sufficient, but some examples of methods or techniques that can be used to determine the genetic makeup of a cell include, without limitation, PCR, RT-PCR, northern blot, southern blot, single nucleotide polymorphism (SNP) analysis, gene-chip expression analysis, serial analysis of gene expression (SAGE), nucleotide sequencing, FAGS, ih situ hybridization, and the lilce.
In some embodiments of the present invention, a cell can be identified by any of the above-mentioned criteria: antigenic determinants, genetic makeup, a combination thereof, or a cell can be identified based upon another set of criteria. h1 some embodiments, at least 0.1%, 1%, at least 10 %, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80 %, at least 90%, at least 95%, or about 100% of the cells are identified.
Methods of identification and determining the number of cells are well l~nown in the art , they include but are not limited to using standard cell detection techniques such as flow cytometry, cell sorting, immunocytochemistry (e.g., staining with tissue specific or cell-marker specific antibodies), FAGS, magnetic activated cell sorting (MACS), by examination of the morphology of cells using light or confocal microscopy, or by measuring changes in gene expression using techniques well known in the art, such as PCR and gene expression profiling. Additionally, relevant determinations can be made by techniques including, but not limited to, optical and electrooptical properties, morphological imaging methods, optophoresis (www.genoptix.com) microwave spectroscopy (Signature Bioscience www.signaturebio.com) and optical tweezers. Other methods may also be employed.
It is known that specific cell-types or cells having particular antigenic determinants can have a deleterious effect on the success rate of cytotherapy.
Therefore, the present invention provides for cytotherapeutic units that have at least one cell type that is excluded. The cell-type that is excluded will not always be the same. In some embodiments, all CD34 positive cells will be excluded. In some other embodiments all CDS positive cells will be excluded. In some other embodiments multiple cell types are excluded. In some applications, it may be acceptable and convenient to reduce, rather than eliminate, selected cell types to improve therapeutic success. Thus, the term "exclusion" or "elimination" as used in this context preferably means at least about 75% reduction in the number of a certain cell type in a cell preparation. Preferably, at least about 90% reduction is achieved, with at least about 95% reduction being even more preferred. Essentially complete elimination is, of course, most desirable, although the same may be achievable in some cases. The foregoing percentage reductions relate to numbers of cells relative to an original population of such cells using any appropriate assay.
Cell types can be excluded or reduced either by selecting cell-containing units which, naturally do not contain them (or many of them) or by employing a process that specifically removes selected cell-types. It is preferred to exclude cell types having antigenic determinants which are inconsistent with the therapeutic modality planned for the cytotherapeutic unit. For example, but not by way of limitation, T-lymphocytes and mature dendritic cells may be excluded to lower the expectation of to graft versus host disease. In the treatment of adrenal leukodysplasia it may be desirable to delete some or all CD8 positive cells.
To be excluded "naturally" means that the preparation of cells that is derived from a source does not contain a specific cell type without further manipulation or contains a very small population of such types. Alternatively, a cell-type can be excluded by a process that is used either before or after the cells are extracted from a source. Processes or methods that are used to exclude a specific cell-type are well known to the art-skilled. Examples of processes or methods include: FACS, centrifugation, immunochromatography, and the like.
In one embodiment, the cells may be sorted using a fluorescence activated cell sorter (FACS). Fluorescence activated cell sorting (FACS) is a well-lcnown method for separating particles, including cells, based on the fluorescent properties of the particles (Kamrach, 1987, Methods Enzymol, 151:150-165). Laser excitation of fluorescent moieties in the individual particles results in a small electrical charge allowing electromagnetic separation of positive and negative particles from a mixture.
In one embodiment, cell surface marker-specific antibodies or ligands are labeled with distinct fluorescent labels. Cells are processed through the cell sorter, allowing separation of cells based on their ability to bind to the antibodies used.
FAGS sorter particles may be directly deposited into individual wells of 96-well or 384-well plates to facilitate separation and cloning. Reagents for cell surface markers or cluster designated reagents are available from a variety of sources including Becton Dickinson and Cell Pro Inc., for example.
Available reagents include but are not limited to reagents for identifying:
CDla; CD2; CD3; CD4; CD4 (Multi-Clone); CD4 v4; CDS; CD7; CD8 (Leu-2a); CD8 (Leu-2b); CD10 (Anti-CALLA); CDlla (Anti-LFA-la); CDllb;
CDllc; CD13; CD14; CD15; CD16 (Leu-lla, 11b, llc); CD18 (Anti-LFA-1(3);
CD19 (Leu-12); CD19(SJ25C1); CD20; CD21(Anti-CRZ); CD22; CD23;
CD25(Anti-IL-2R); CD26; CD27; CD28; CD31(Anti-PECAM-1); CD33;
CD34(Anti-HPCA-1&2); CD38; CD42a(Anti-gpIX); CD44; CD45(Anti-Hle-1);
CD45RA; CD45R0; CD49d(Anti-VLA-a4); CD54; CD56(MY31);
CD56(NCAM16.2); CD57; CD58(Anti-LFA-3); CD61; CD62P; CD62L(Leu-8);
CD69; CD71; CD80(Anti-BB1B7); CD95; CD117; CD122(Anti-IL-2Rp75);
CD123(Anti-IL-3Ra); CD134(Ox40); CD154(CD40L); CD158a; CD161; Lineage Cocktail 1 (linl) FITC and others now known or hereafter discovered.
Non-cluster designated reagents include: Anti-BrdU; Anti-Cytokeratin (CAM
5.2); Anti-HER-2/neu; Anti-HLA-DP; Anti-HLA-DQ; Anti-HLA-DR; Anti-Hu KIR (NKB1); Anti-IgA2; Anti-IgD; Anti-IgG; Anti-IgM (Ig Heavy Chain); Anti-Kappa (Ig Light Chain); Anti-Kappa F(ab')2; Anti-Lambda (Ig Light Chain); Anti-Lambda F(ab')2; Anti-P-glycoprotein (P-gp); Anti-TCR a/(3-1 (WT31); Anti-TCR-y/8-1; PAC-1; Lineage Coclctail 1 (linl) FITC. The skilled artisan will use those reagents required for his/her particular needs in order to optimize the desired cytotherapeutic unit or tailor it for a particular patient or use.
In another embodiment, magnetic beads can be used to separate cells. The cells may be sorted using a magnetic activated cell sorting (MACS) technique, a method for separating particles based on their ability to bind magnetic beads (0.5-100~,m diameter). A variety of useful modifications can be performed on the magnetic microspheres, including the covalent addition of an antibody which specifically recognizes a cell-solid phase surface molecule or hapten. A
magnetic field is then applied, to physically manipulate the selected beads. The beads are then mixed with the cells to allow binding. Cells are then passed through a magnetic field to separate out cells having cell surface markers. These cells can then isolated and re-mixed with magnetic beads coupled to an antibody against additional cell surface markers. The cells are again passed through a magnetic field, isolating cells that bound both the antibodies. Such cells can then be diluted into separate dishes, such as microtiter dishes for clonal isolation, if desired.
Knowing the composition of the cytotherapeutic unit will help fulfill the long-felt need of a reliable and certified cytotherapeutic unit. In addition to the composition of the unit, it can be useful to know the numbers of at least some of the cells in the cytotherapeutic unit. In some embodiments, just the numbers of cells will be known without lrnowing the specific identity of any of the cells. In some other embodiments, the numbers of cells will be known, but also the numbers of the identified cells will be lcnown. To determine the number of cells in total is well known to those of ordinary skill in the art. Examples of equipment that can be used to count cells are a machine that performs FACS or flow cytometry, or a much simpler piece of equipment, a hemacytometer. Often the number of the cells will be determined at the same time the identities are determined, but the numbers can also be determined before or after the identities of some of the potent cells are determined.
By knowing the number of the cells present in a cytotherapeutic unit this will give a person using the unit the lcnowledge of what is being administered, something that is sorely lacking in present cytotherapies.
The knowledge of the numbers of total cells and also the numbers of specific cell types in a cytotherapeutic unit can be used to supplement the unit with additional cells or cell types so that a minimum number of cells or a minimum number of a specific cell type can be present in the unit. It is thought that the diverse responses seen in cytotherapy is in part due to the varying number of cells recovered from a source using the cellular preparation techniques in use today.
By identifying and counting the cells this will allow a more thorough analysis of what is required for a successful treatment as well as the ability to perform a thorough and complete analysis on the importance of a specific cell type in a cellular preparation.
Cytotherapeutic units can now be prepared that have a minimum numbers of preselected cells. It is also now possible to ensure that other cell types are excluded from the units. In some embodiments the cytotherapeutic unit will comprise at least about 100 selected potent cells. Such units having at least about 1,000 such cells are preferred, with at least about 10,000 being more preferred. Greater numbers of selected cells are still more preferred, especially when it is intended that the unit be administered to the same or different individuals a plurality of times. Thus, selected cell populations greater than about 100,000 or even about 500,000 can be useful. It is preferred that some or all of the cells in the unit be identified through assay and that the same be reflected in a certification of such presence. This certification ensures uniform and effective therapeutic application.
In some embodiments of the present invention, the cytotherapeutic units will have a minimum number of different, specific cell types. Advantages to having a minimum number of specific cell types are that it may improve the efficacy of the cytotherapeutic unit. For example, the cytotherapeutic unit could be assayed to comprise at least about 1,000 OCT4 positive cells, either with or without lrnown quantities of other desirable cell types. In other embodiments, the unit may be caused to comprise specific percentages of CD34 positive cells, measured by reference to all nucleated cells in the preparation. Thus, such preparations may contain at least 0.01%, 0.1%, 1%, 10%, 20%, 30%, 40%, 50%, 60%, 70 %, 80%, 90%, 95% or other percentages of CD34 positive cells may be made. Similar, known percentages of cells having other antigenic determinants or specific factors may, lilcewise, be created.
Other embodiments of the present invention provide for cytotherapeutic omits comprising cells that have been derived from at least one source, wherein the source's cells have been separated into components. As used herein, the term "components" is synonymous to cell-types, identified cells, and the lilce. Methods to separate cellular preparations into components that are well known to those of skill in the art include, without limitation, FACS, centrifugation, chromatography, HPLC, FPLC, and the like.
Thus, cytotherapeutic uiuts can comprise components that axe recombined. In some embodiments, at least one component is used in a cytotherapeutic unit. In some other embodiments, at least two, at least three, at least 4, at least S, at least 10, at least 100 components are recombined to make the cytotherapeutic unit. It is preferred that the components of each source be known in terms of identity and relative numbers, with some cell types preferably being excluded from some or all of the components.
It may be seen that the different components may be maintained separately, e.g.
frozen, and that the same may form a "formulary" or "library" of cells of known identity and abundance for formulation into combined cytotherapeutic units.
Separating the respective cellular preparations into components allows a cytotherapeutic unit to be created that has a specific composition both in terms of cells present and in types of cells excluded. Additionally, this allows an existing cytotherapeutic unit to be supplemented with a specific cell-type or component as may be indicated for a specific therapeutic modality.
Thus, cytotherapeutic units"of the invention may be seen to comprise cells derived from one source or from many sources. Contrary to prevailing practice, it is believed that there are great benefits to providing cells from a plurality of sources and that therapeutic benefit and efficacy will derive therefrom. In some embodiments, the cells are derived from multiple sources and may derive from multiple organs in such sources. As used herein, the term "source" refers to any organism, tissue, or organ from which cells are derived or extracted. In some embodiments, the sources are fetal cord blood, fetal tissue, placenta, postpartum placenta, postpartum placenta perfusate, or a mixture thereof. It is well known to those of ordinary skill how to extract cells from different tissues or organs. Methods to extract cells from fetal cord blood can be -found in, for example in U.S. Patent No. 5,372,581, entitled "Method and apparatus for placental blood collection," issued December 13, 1994; Hessel et al., U.S.
Patent No. 5,415,665, entitled "Umbilical cord clamping, cutting, and blood collecting device and method", issued May 16, 1995. The needle or cannula is usually placed in the umbilical vein and the placenta is gently massaged to aid in draining cord blood from the placenta. Methods to extract cells from placenta, post-partum placenta, or post-partum placenta perfusate can be found in, for example, International Patent Publications WO 02/46373 and WO 02/064755, each of which are herein incorporated by reference in their entireties.
In another embodiment, the cells are stimulated to proliferate, for example, by administration of erythropoietin, cytoleines, lympholcines, interferons, colony stimulating factors (CSF's), interferons, chemolcines, interleukins, recombinant human hematopoietic growth factors including ligands, stem cell factors, thrombopoeitin (TPO), interleulcins, and granulocyte colony-stimulating factor (G-CSF) or other growth factors.
In another embodiment; cells are genetically engineered, for example, using a viral vector such as an adenoviral or retroviral vector, or by using mechanical means such as liposomal or chemical mediated uptake of the DNA.
A vector containing a transgene can be introduced into a cell of interest by methods well lcnown in the art, e.g:, transfection, transformation, transduction, electroporation, infection, microinjection, cell fusion, DEAF extran, calcium phosphate precipitation, liposomes, LIPOFECTINTM, lysosome fusion, synthetic cationic lipids, use of a gene gun or a DNA vector transporter, such that the tra~isgene is transmitted to daughter cells, e.g., the daughter embryonic-like stem cells or progenitor cells produced by the division of an embryonic-like stem cell. For various techniques for transformation or transfection of mammalian cells, see Keown et al., 1990, Methods Enzymol. 185:527-37; Sambrook et al., 2001, Molecular Cloning, A
Laboratory Manual, Third Edition, Cold Spring Harbor Laboratory Press, N.Y.
The cytotherapeutic units will preferably comprise minimum numbers of preselected types of potent cells and be certified as such. As used herein, "preselected" refers to the process of selecting the types of potent cells that are to be in the cytotherapeutic unit before it is administered. Preselecting the types of potent cells that will have a minimum number of those cells in the cytotherapeutic unit allows the cytotherapeutic unit to be tailored to a composition desired to achieve a specific therapeutic result in an individual or class of individuals.
Likewise, certification as to the absence of other preselected types of cells is preferred for similar reasons.
The plurality of potent cells and of cell types present in the cytotherapeutic units of the invention are selected to render the units suitable for therapy for an indicated disease state or condition. As used herein, the phrase "selected to render"
refers to the process of deciding that a cytotherapeutic unit comprising a plurality of potent cells is suitable for therapy. This decision can be based on the numbers of potent cells present in the cytotherapeutic unit. As discussed hereinbefore, the number of cells appears to be critical for the success rate of treating an individual or patient with cytotherapy. Therefore, not all cytotherapeutic units may be suitable for therapy for an indicated disease state or condition. Additionally, the types of potent cells will also aid in the decision process on whether or not a cytotherapeutic unit is suitable for therapy. Certain types of potent cells card be detrimental or beneficial to the treatment of a specific disease state or condition. Thus, the types of cells present in the unit can be another factor that is used to select a unit suitable for therapy. The criteria that are used to select a unit that is suitable for therapy is not specific to those mentioned above. Any set of criteria can be used to decide whether or not a plurality of potent cells present in a cytotherapeutic unit are selected to render the unit suitable for therapy of an indicated disease state or condition.
The present invention provides for cytotherapeutic units wherein at least some of the potent cells present in the unt are identified and counted. However, for the units to be relied upon in scientific;research and to be used as a cytotherapeutic the units' contents must be preferably assayed to ensure the accuracy of the identities and numbers. The assays can be done by the same group, individual, or machine that had determined the identities and the numbers of at least some of the potent cells in the cytotherapeutic units. However, the assays can be performed by a different individual, group, or machine that had determined the identities and numbers of some of the potent cells. In some embodiments, only one assay needs to be performed to ensure the accuracy of the identities and the numbers. In some other embodiments, at least 2, at least 5, or at least 10 assays are performed to ensure the accuracy of the identities and the numbers of the potent cells. The types of assays to be done can be the same assay that was used to determine the numbers and the identities previously.
In some other embodiments, different assays are used to ensure the accuracy of the numbers and identities of some of the potent cells. Some assays that can be used to ensure the accuracy include, without limitation, ELISA, FAGS, western blot, and the like.
In some other embodiments, the provider of the unit certifies the accuracy of the assay. As used herein, the term "provider" refers to an individual, business, or facility that is providing the cytotherapeutic unit to the individual that is using the unit. In some embodiments, the certification comprises a m.-itten statement indicating that the assay was performed correctly and that the results are correct. In some other embodiments, the certification comprises results from an assay done on a positive control to show that the assay was functioning properly. In some other embodiments, the certification comprises both the results of the positive control and a written statement that the assay was functioning properly. In some further embodiments, the certification comprises a list of the types of potent cells that have been excluded from the cytotherapeutic unit. In some further embodiments, the certification comprises a list of at least some of the types of potent cells that are contained in the cytotherapeutic u~zit. In some embodiments, the certification comprises the numbers of all the cells. In some embodiments, the certification further comprises the quantity of at least some of the specific cell types. W some other embodiments, the certification comprises a list of the types of at least some of the potent cells that have been added to the unit to supplement the potent cells so that the unit comprises minimum numbers of potent cells.
The present invention also provides for bits for the treatment of a person suspected of having a disease state or condition comprising a cytotherapeutic unit comprising a plurality of potent cells with the content of the unit being known with respect to the identities and numbers of at least some of the potent cells.
Additionally, the cytotherapeutic unit is assayed to ensure the accuracy of the identities and numbers of the potent cells. The lcits further comprise a certification of the accuracy of the assay. In some embodiments, the bits comprise a cytotherapeutic unit having minimum numbers of identified potent cells and a certification of the potent cell composition of the unit. In some other embodiments, the kits comprise cytotherapeutic units that have at least one cell-type that has been excluded.
The present invention also provides for methods of treating a disease state or condition in a mammal. The methods comprise administering to the mammal a therapeutically effective amount of a composition comprising a cytotherapeutic unit comprising potent cells, wherein some of the potent cells are known with respect to their identities and numbers. The unit is also assayed to ensure the accuracy of the identities and the numbers. In some other embodiments, the cytotherapeutic unit comprises minimum numbers of preselected types of potent cells.
A therapeutically effective amount for a mammal can vary, but for example could be approximately 0.01 cytotherapeutic muts/lcg to 100 units/lcg. The cytotherapeutic unit can be administered rapidly or slowly to the mammal. In some embodiments, the cytotherapeutic unit is administered at a rate of approximately 0.01 ~,l /minute, and in other embodiments, the unit is administered at a rate of approximately 100,000 ml/minute. The unit can be administered, for example, intravenously, subcutaneously, intramuscularly, orally, or rectally. In some embodiments, the unit is administered multiple times to the mammal at different times. In some other embodiments, cytotherapeutic units derived from different sources or different individuals are administered to the mammal.
The potential uses for cytotherapeutic units are limitless, but some examples of disease states or conditions that cytotherapeutic units can be used to treat include cancer, acute leul~emia, chronic leul~emia as well as other cancers presently treated with bone marrow or cord blood cell transplants, myelodysplastic syndrome, stem cell disorder, myeloproliferative disorder, lymphoproliferative disorder, phagocyte disorder, liposomal storage disorder, histiocytic disorder, inherited erythrocyte abnormality, congenital (inherited) immune system disorder, inherited platelet abnormality, plasma cell disorder, Lesch-Nyhan Syndrome, Cartilage-Hair Hypoplasia, Glanzmann Thrombastenia, osteoporosis, breast caaicer, Ewing Sarcoma, neuroblastoma, renal cell carcinoma, lung cancer, Alzheimer's disease, liver disease, hepatitis, Parl~inson's disease, vision loss, memory loss, and the life.
The cytotherapeutic units may be optimized for enzyme replacement therapy to treat specific diseases or conditions, including, but not limited to, lysosomal storage diseases, such as Tay-Sachs, Niemann-Picl~, Fabry's, Gaucher's, Hunter's, and Hurler's syndromes, as well as other gangliosidoses, mucopolysaccharidoses, and glycogenoses. The cytotherapeutic units in this case may be certified that the cells have been assayed to contain the desired number of cells capable of producing the necessary enzyme. Said unit may contain either allogeneic cells containing the functional endogenous gene of the desired enzyme, autologous cells containing exogenous copies of the desired gene or a combination of both.
In other embodiments, the cells may be used as autologous or heterologous transgene caxriers in gene therapy to correct inborn errors of metabolism such as adrenoleul~odystrophy, cystic fibrosis, glycogen storage disease, hypothyroidism, sicple cell anemia, Pearson syndrome, Pompe's disease, phenyllcetonuria (PKI~, Tay-Sachs disease, porphyrias, maple syrup urine disease, homocystinuria, mucopolypsaccharidoses, chronic granulomatous disease, and tyrosinemia or to treat cancer, tumors or other pathological conditions.
The citation of any publication is for its disclosure prior to the filing date and should not be construed as an aclinission that present invention is not entitled to antedate such publication by virtue of prior invention.
The present invention is not to be limited in scope by the specific embodiments described herein. hideed, various modifications of the invention in addition to those described herein will become apparent to those spilled in the art from the foregoing description. Such modifications are intended to fall within the scope of the appended claims.
All references cited herein are incorporated herein by reference in their entirety and for all purposes to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety for;all purposes.
An adult having acute myelogenous leukemia (AML) is in need of hematopoetic reconstitution by way of a cell transplant. The patient undergoes traditional chemotherapy followed by conventional preparation for tra~zsplant as determined by the patient's health care provider but includes destroying the diseased bone marrow. The patient's weight is determined. Appropriate HLA typing has been done by conventional methods. Based on these parameters, which include the disease to be treated, the patient's body weight and HLA matching, the transplanter requests and is provided with a cytotherapeutic unit comprising a plurality of potent nucleated cells; the content of said mlit being l~nown with respect to the identities and numbers at least some of said plurality; the unit being assayed to ensure the accuracy of said identities and numbers, which is certified. In particular, the unit is certified to contain about 1.4 x 10~ nucleated cells per l~ilogram of the patient's body weight.
Additional certified information includes HLA information. Because the patient suffers from AML, the cytotherapeutic unit contains no less than one (1) percent of CD34+
of the total nucleated cells and no less than 2.5 percent CD8+ cells to minimize graft versus tumor effect. In this case the transplanter requests twice the total number of cells needed for transplant (1.4 x 10' nucleated cells multiplied by the patient's weight in ltilograms x2). The transplanter requests the lx amount just prior to the transplant in order to have the number of cells suitable for this transplant. The second half of the cells is to be shipped in the event that a second transplant becomes necessary.
Accordingly, the second cytotherapeutic unit is the same as that to be used in the initial transplant. Alternatively, the transplanter may request, based on alterations in the patient's weight, severity of disease or even changes in recommended treatment, that the second cytotherapeutic unit be altered in the appropriate mamler (increased number of CD34 positive cells, etc.) and certified. The transplant is performed in the same mamzer conventionally used by the transplanter.
A child having siclcle cell anemia is in need of a cell transplant. It is determined that 1.7 x 10' nucleated cells per l~ilogram of body weight of the child is needed. Appropriate HLA typing is done by conventional methods. It is determined that the cytotherapeutic unit must have no less than 1% CD34+ cells of the total nucleated cells. Said CD34+ cells are further described in a ratio of 2:1 as CD34+/CD33+: CD34+/CD33- A cytotherapeutic unit having these parameters is provided. This unit comprises cells derived from cord blood as well as pluripotential placental cells such as those described in WO 02/064755, which are derived in the manner described in W002/064755. The ratio of CD34+/ CD33+
cells is 2:1 to CD34+/ CD33-, a fact which is ascertained by assay and certified as being accurate. The certified cells are determined using FACS; based on the fluorescent properties of the particles, cell surface marker-specific antibodies or ligands are labeled with distinct fluorescent labels. Cells are processed through the cell sorter, allowing separation of cells based on their ability to bind to the antibodies used. Cell surface marker-specific antibodies may be purchased from any company selling such reagents, including Becton Dickinson, for example. The transplant is performed in the same manner conventionally used by the transplanter.
A child suffers from adrenal leukodysplasia. It is determined that a cellular transplant is appropriate. It is determined that 2 x 10' nucleated cells (derived from cord blood by a conventional technique) per kilogram of body weight of the child is needed. Appropriate HLA typing is done by conventional methods. A
cytotherapeutic unit having these parameters is provided. In particular, the unit is certified to contain no less than 0.25% of CD34+/ CD38- cells and with no less than 0.5% depletion of CD8+ cells of the total nucleated cells. The transplant is performed in the same manner conventionally used by the transplanter.
Claims (53)
1. A cytotherapeutic unit comprising a plurality of potent cells; the content of said unit being known with respect to the identities and numbers at least some of said plurality; the unit being assayed to ensure the accuracy of said identities and numbers.
2. The cytotherapeutic unit of claim 1 wherein the accuracy of the assay is certified by the provider of the unit.
3. The cytotherapeutic unit of claim 1 wherein the potent cells for which the identities and numbers are known are pluripotent cells.
4. The cytotherapeutic unit of claim 1 wherein said identities reflect the presence or absence of at least one antigenic determinant on identified cells.
5. The cytotherapeutic unit of claim 1 wherein said potent cells are obtained from fetal cord blood or other fetal tissue.
6. The cytotherapeutic unit of claim 1 wherein said potent cells are obtained from fetal cord blood.
7. The cytotherapeutic unit of claim 1 wherein said potent cells are obtained from placenta.
8. The cytotherapeutic unit of claim 1 wherein said potent cells are obtained from postpartum placenta.
9. The cytotherapeutic unit of claim 1 wherein said potent cells are obtained from postpartum placenta perfusate.
10. The cytotherapeutic unit of claim 1 wherein potent cells for which the identities and numbers are known comprise at least some of cells exhibiting CD34, CD8, CD10, OCT4.
11. The cytotherapeutic unit of claim 1 wherein potent cells are derived from a plurality of sources.
12. The cytotherapeutic unit of claim 1 wherein potent cells are derived from at least two individuals.
13. The cytotherapeutic unit of claim 1 wherein potent cells are derived from at least 5 individuals
14. The cytotherapeutic unit of claim 1 wherein potent cells are genetically modified.
15. The cytotherapeutic unit of claim 1 wherein at least one type of cell is excluded from the unit.
16. The cytotherapeutic unit of claim 1 wherein the plurality of potent cells is selected to render the cytotherapeutic unit suitable for therapy for an indicated disease state or condition.
17. The cytotherapeutic unit of claim 16 wherein at least one type of cell is excluded from the unit.
18. A cytotherapeutic unit comprising minimum numbers of preselected types of potent cells.
19. The cytotherapeutic unit of claim 18 which has been assayed to ensure accuracy of its contents of preselected types of potent cells.
20. The cytotherapeutic unit of claim 18 wherein the contents of preselected potent cells is certified.
21. The cytotherapeutic unit of claim 18 wherein at least one type of cell is excluded from the unit.
22. The cytotherapeutic unit of claim 21 wherein the contents of preselected potent cells and the absence the types of cells to be excluded is certified.
23. The cytotherapeutic unit of Claim 18, wherein said certification is of a plurality of potent cell types, said plurality and the numbers of each of said plurality being selected to render the cytotherapeutic unit suitable for therapy for an indicated disease state or condition.
24. The cytotherapeutic unit of Claim 23, wherein said certification is of a plurality of potent cell types, said plurality and the numbers of each of said plurality being selected as well as the types of cells excluded renders the cytotherapeutic unit suitable for therapy for an indicated disease state or condition.
25. The cytotherapeutic unit of Claim 18 where at least some potent cells are genetically modified.
26. A kit for treatment of a person suspected of having a disease state or condition comprising a cytotherapeutic unit comprising a plurality of potent cells; the content of said unit being known with respect to the identities and numbers at least some of said plurality; the unit being assayed to ensure the accuracy of said identities and numbers;
and a certification of the accuracy of the assay.
and a certification of the accuracy of the assay.
27. The kit of claim 26 wherein at least one type of cell has been excluded from the cytotherapeutic unit.
28. A kit for treatment of a person suspected of having a disease state or condition comprising a cytotherapeutic unit having minimum numbers of identified potent cells and a certification of the potent cell composition of the unit.
29. The kit of claim 28 wherein at least one type of cell has been excluded from the cytotherapeutic unit.
30. The kit of claim 28 wherein at least some cells are genetically modified.
31. A cytotherapeutic unit comprising cells derived from umbilical cord blood, placenta, or a mixture thereof, wherein at least one type of cell has been removed from the unit.
32. The cytotherapeutic unit of claim 31 wherein a plurality of cell types have been removed from the unit.
33. The cytotherapeutic unit of claim 31 wherein at least some cells of the unit are genetically modified.
34. A cytotherapeutic unit comprising cells derived from umbilical cord blood, placenta, or a mixture thereof, said cells comprising a plurality of different types, at least some of the different types having been separated into components and recombined into said unit.
35. The cytotherapeutic unit of claim 34, wherein said separated cell types have been frozen separately.
36. The cytotherapeutic unit of claim 34, in a frozen state.
37. The cytotherapeutic unit of claim 34, wherein said separated cell types have been characterized.
38. The cytotherapeutic unit of claim 34, wherein said separated cell types have been genetically modified
39. A method of treating a disease in a mammal comprising:
Administering to said mammal a therapeutically effective amount of a composition comprising: a cytotherapeutic unit comprising a plurality of potent cells; the content of said unit being known with respect to the identities and numbers of at least some of said plurality; the unit being assayed to ensure the accuracy of said identities and numbers.
Administering to said mammal a therapeutically effective amount of a composition comprising: a cytotherapeutic unit comprising a plurality of potent cells; the content of said unit being known with respect to the identities and numbers of at least some of said plurality; the unit being assayed to ensure the accuracy of said identities and numbers.
40. The method of claim 39, wherein the cytotherapeutic unit comprises minimum numbers of preselected types of potent cells.
41. The method of claim 39, wherein the accuracy of said identities and numbers is certified.
42. The method of claim 39, wherein the cytotherapeutic unit is derived from post-partum placenta.
43. The method of claim 39, wherein the cytotherapeutic unit is derived from post-partum placenta perfusate.
44. The method of claim 39, wherein said unit comprises at least one cell that is autologous.
45. The method of claim 39, wherein said unit comprises at least one cell that is exogenous.
46. The method of claim 39, wherein said unit is administered multiple times.
47. The method of claim 39, wherein said method further comprises administering multiples of said units that are derived from different individuals.
48. The method of claim 39, wherein said method further comprises administering multiples of said units that are derived from different sources.
49. The method of claim 39, wherein said method further comprises administering multiple units that are genetically modified.
50. A library of cytotherapeutic units, each unit member of said library comprising a plurality of potent cells; the content of each of said units being known with respect to the identities and numbers at least some of the plurality of potent cells comprising said unit; each of said units being assayed to ensure the accuracy of said identities and numbers.
51. A method of treatment of a patient in need of cytotherapeutic treatment comprising selecting from a library of cytotherapeutic units at least two unit members of said library; combining aliquots from said unit members to form a treatment unit and administering said treatment unit to the patient.
52. The method of claim 51 wherein each of the unit members of the library has been assayed to determine the identity and numbers of potent cells present in said unit member.
53. The method of claim 51 wherein at least one of said unit members of the library has been reduced in at least one selected cell population.
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PCT/US2003/038143 WO2004047770A2 (en) | 2002-11-26 | 2003-11-25 | Cytotherapeutics, cytotherapeutic units and methods for treatments using them |
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Families Citing this family (50)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
KR100915482B1 (en) | 2000-12-06 | 2009-09-03 | 하리리 로버트 제이 | Method of collecting placental stem cells |
US7311905B2 (en) | 2002-02-13 | 2007-12-25 | Anthrogenesis Corporation | Embryonic-like stem cells derived from post-partum mammalian placenta, and uses and methods of treatment using said cells |
US20080152629A1 (en) * | 2000-12-06 | 2008-06-26 | James Edinger | Placental stem cell populations |
EP1362095B1 (en) * | 2001-02-14 | 2015-05-27 | Anthrogenesis Corporation | Post-partum mammalian placenta, its use and placental stem cells therefrom |
NZ528035A (en) * | 2001-02-14 | 2005-07-29 | Robert J Hariri | Renovation and repopulation of decellularized tissues and cadaveric organs by stem cells |
AU2002258734A1 (en) * | 2001-04-13 | 2002-10-28 | Wyeth Holdings Corporation | Removal of bacterial endotoxin in a protein solution by immobilized metal affinity chromatography |
US7498171B2 (en) | 2002-04-12 | 2009-03-03 | Anthrogenesis Corporation | Modulation of stem and progenitor cell differentiation, assays, and uses thereof |
CA2481385A1 (en) * | 2002-04-12 | 2003-10-23 | Celgene Corporation | Modulation of stem and progenitor cell differentiation, assays, and uses thereof |
KR20050000398A (en) * | 2002-04-12 | 2005-01-03 | 셀진 코포레이션 | Methods for identification of modulators of angiogenesis, compounds discovered thereby, and methods of treatment using the compounds |
EP1571910A4 (en) | 2002-11-26 | 2009-10-28 | Anthrogenesis Corp | Cytotherapeutics, cytotherapeutic units and methods for treatments using them |
GB0321337D0 (en) * | 2003-09-11 | 2003-10-15 | Massone Mobile Advertising Sys | Method and system for distributing advertisements |
NZ550027A (en) * | 2004-03-26 | 2009-03-31 | Celgene Corp | Systems and methods for providing a stem cell bank |
CN101080486B (en) | 2004-04-23 | 2012-05-16 | 佰欧益股份有限公司 | Multi-lineage progenitor cells |
US7622108B2 (en) * | 2004-04-23 | 2009-11-24 | Bioe, Inc. | Multi-lineage progenitor cells |
WO2005113751A1 (en) | 2004-05-14 | 2005-12-01 | Becton, Dickinson And Company | Cell culture environments for the serum-free expansion of mesenchymal stem cells |
AU2006203879A1 (en) * | 2005-01-04 | 2006-07-13 | Stemcells California, Inc. | Methods for the treatment of lysosomal storage disorders |
ES2452595T3 (en) | 2005-10-13 | 2014-04-02 | Anthrogenesis Corporation | Immunomodulation using placental stem cells |
EP2368973A1 (en) * | 2005-10-13 | 2011-09-28 | Anthrogenesis Corporation | Production Of Oligodendrocytes From Placenta-Derived Stem Cells |
EP1974013A2 (en) | 2005-12-29 | 2008-10-01 | Anthrogenesis Corporation | Improved composition for collecting and preserving placental stem cells and methods of using the composition |
US8455250B2 (en) * | 2005-12-29 | 2013-06-04 | Anthrogenesis Corporation | Co-culture of placental stem cells and stem cells from a second source |
PL2471904T3 (en) | 2005-12-29 | 2019-08-30 | Celularity, Inc. | Placental stem cell populations |
EP2019858B1 (en) * | 2006-04-17 | 2012-06-13 | BioE LLC | Differentiation of multi-lineage progenitor cells to respiratory epithelial cells |
ZA200810412B (en) * | 2006-06-09 | 2010-03-31 | Anthrogenesis Corp | Placental niche and use thereof to culture stem cells |
US7993918B2 (en) | 2006-08-04 | 2011-08-09 | Anthrogenesis Corporation | Tumor suppression using placental stem cells |
US8372437B2 (en) | 2006-08-17 | 2013-02-12 | Mimedx Group, Inc. | Placental tissue grafts |
CA2850793A1 (en) | 2006-10-23 | 2008-05-02 | Anthrogenesis Corporation | Methods and compositions for treatment of bone defects with placental cell populations |
AU2008216749B2 (en) | 2007-02-12 | 2014-03-13 | Celularity Inc. | Treatment of inflammatory diseases using placental stem cells |
EP2129775A1 (en) | 2007-02-12 | 2009-12-09 | Anthrogenesis Corporation | Hepatocytes and chondrocytes from adherent placental stem cells; and cd34+, cd45- placental stem cell-enriched cell populations |
WO2008156659A1 (en) | 2007-06-18 | 2008-12-24 | Children's Hospital & Research Center At Oakland | Method of isolating stem and progenitor cells from placenta |
US9200253B1 (en) | 2007-08-06 | 2015-12-01 | Anthrogenesis Corporation | Method of producing erythrocytes |
US8357403B2 (en) | 2007-09-07 | 2013-01-22 | Mimedx Group, Inc. | Placental tissue grafts |
EP2783692B1 (en) | 2007-09-28 | 2019-01-02 | Celularity, Inc. | Tumor suppression using human placental perfusate and human placenta-derived intermediate natural killer cells |
CN105796602A (en) | 2008-08-20 | 2016-07-27 | 人类起源公司 | Treatment of stroke using isolated placental cells |
MX2011001990A (en) | 2008-08-20 | 2011-03-29 | Anthrogenesis Corp | Improved cell composition and methods of making the same. |
CN102176919A (en) | 2008-08-22 | 2011-09-07 | 人类起源公司 | Methods and compositions for treatment of bone defects with placental cell populations |
KR20110086176A (en) | 2008-11-19 | 2011-07-27 | 안트로제네시스 코포레이션 | Amnion derived adherent cells |
US8771677B2 (en) | 2008-12-29 | 2014-07-08 | Vladimir B Serikov | Colony-forming unit cell of human chorion and method to obtain and use thereof |
CA2767014C (en) | 2009-07-02 | 2022-01-25 | Anthrogenesis Corporation | Method of producing erythrocytes without feeder cells |
AU2010276201B2 (en) * | 2009-07-21 | 2013-10-17 | Abt Holding Company | Use of stem cells to reduce leukocyte extravasation |
ES2646750T3 (en) | 2010-01-26 | 2017-12-15 | Anthrogenesis Corporation | Treatment of bone-related cancers using placental stem cells |
WO2011106476A1 (en) * | 2010-02-25 | 2011-09-01 | Abt Holding Company | Modulation of microglia activation |
SI2556145T1 (en) | 2010-04-07 | 2017-01-31 | Anthrogenesis Corporation | Angiogenesis using placental stem cells |
KR20130092394A (en) | 2010-04-08 | 2013-08-20 | 안트로제네시스 코포레이션 | Treatment of sarcoidosis using placental stem cells |
NZ605505A (en) | 2010-07-13 | 2015-02-27 | Anthrogenesis Corp | Methods of generating natural killer cells |
US8574899B2 (en) | 2010-12-22 | 2013-11-05 | Vladimir B Serikov | Methods for augmentation collection of placental hematopoietic stem cells and uses thereof |
AR093183A1 (en) | 2010-12-31 | 2015-05-27 | Anthrogenesis Corp | INCREASE IN THE POWER OF PLACENTA MOTHER CELLS USING MODULATING RNA MOLECULES |
EP3443968A1 (en) | 2011-06-01 | 2019-02-20 | Celularity, Inc. | Treatment of pain using placental stem cells |
US9925221B2 (en) | 2011-09-09 | 2018-03-27 | Celularity, Inc. | Treatment of amyotrophic lateral sclerosis using placental stem cells |
EP2623978A1 (en) | 2012-02-03 | 2013-08-07 | Charité - Universitätsmedizin Berlin | CD8+ T-cell subsets as markers for prediction of delayed fracture healing |
AU2014215458A1 (en) | 2013-02-05 | 2015-08-13 | Anthrogenesis Corporation | Natural killer cells from placenta |
Family Cites Families (219)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US3862002A (en) * | 1962-05-08 | 1975-01-21 | Sanfar Lab Inc | Production of physiologically active placental substances |
US4008719A (en) * | 1976-02-02 | 1977-02-22 | Alza Corporation | Osmotic system having laminar arrangement for programming delivery of active agent |
US5391485A (en) * | 1985-08-06 | 1995-02-21 | Immunex Corporation | DNAs encoding analog GM-CSF molecules displaying resistance to proteases which cleave at adjacent dibasic residues |
JPS63500636A (en) * | 1985-08-23 | 1988-03-10 | 麒麟麦酒株式会社 | DNA encoding multipotent granulocyte colony stimulating factor |
US4810643A (en) * | 1985-08-23 | 1989-03-07 | Kirin- Amgen Inc. | Production of pluripotent granulocyte colony-stimulating factor |
US4829000A (en) | 1985-08-30 | 1989-05-09 | The United States Of America As Represented By The Secretary Of The Department Of Health And Human Services | Reconstituted basement membrane complex with biological activity |
US4798824A (en) * | 1985-10-03 | 1989-01-17 | Wisconsin Alumni Research Foundation | Perfusate for the preservation of organs |
US5863531A (en) * | 1986-04-18 | 1999-01-26 | Advanced Tissue Sciences, Inc. | In vitro preparation of tubular tissue structures by stromal cell culture on a three-dimensional framework |
US5902741A (en) | 1986-04-18 | 1999-05-11 | Advanced Tissue Sciences, Inc. | Three-dimensional cartilage cultures |
US5004681B1 (en) | 1987-11-12 | 2000-04-11 | Biocyte Corp | Preservation of fetal and neonatal hematopoietic stem and progenitor cells of the blood |
US5192553A (en) * | 1987-11-12 | 1993-03-09 | Biocyte Corporation | Isolation and preservation of fetal and neonatal hematopoietic stem and progenitor cells of the blood and methods of therapeutic use |
US5284766A (en) * | 1989-02-10 | 1994-02-08 | Kao Corporation | Bed material for cell culture |
FR2646438B1 (en) | 1989-03-20 | 2007-11-02 | Pasteur Institut | A METHOD FOR SPECIFIC REPLACEMENT OF A COPY OF A GENE PRESENT IN THE RECEIVER GENOME BY INTEGRATION OF A GENE DIFFERENT FROM THAT OR INTEGRATION |
US5605822A (en) * | 1989-06-15 | 1997-02-25 | The Regents Of The University Of Michigan | Methods, compositions and devices for growing human hematopoietic cells |
US5763266A (en) | 1989-06-15 | 1998-06-09 | The Regents Of The University Of Michigan | Methods, compositions and devices for maintaining and growing human stem and/or hematopoietics cells |
US5437994A (en) | 1989-06-15 | 1995-08-01 | Regents Of The University Of Michigan | Method for the ex vivo replication of stem cells, for the optimization of hematopoietic progenitor cell cultures, and for increasing the metabolism, GM-CSF secretion and/or IL-6 secretion of human stromal cells |
US5399493A (en) | 1989-06-15 | 1995-03-21 | The Regents Of The University Of Michigan | Methods and compositions for the optimization of human hematopoietic progenitor cell cultures |
US5635386A (en) | 1989-06-15 | 1997-06-03 | The Regents Of The University Of Michigan | Methods for regulating the specific lineages of cells produced in a human hematopoietic cell culture |
DE69034263D1 (en) | 1989-07-25 | 2009-04-02 | Cell Genesys Inc | Homologous recombination for universal donor cells and mammalian chimeric cells |
US5464764A (en) * | 1989-08-22 | 1995-11-07 | University Of Utah Research Foundation | Positive-negative selection methods and vectors |
DK0747485T3 (en) | 1989-11-06 | 1999-08-16 | Cell Genesys Inc | Preparation of proteins using homologous recombination |
US5272071A (en) | 1989-12-22 | 1993-12-21 | Applied Research Systems Ars Holding N.V. | Method for the modification of the expression characteristics of an endogenous gene of a given cell line |
US5061620A (en) | 1990-03-30 | 1991-10-29 | Systemix, Inc. | Human hematopoietic stem cell |
US5635387A (en) | 1990-04-23 | 1997-06-03 | Cellpro, Inc. | Methods and device for culturing human hematopoietic cells and their precursors |
US5733566A (en) * | 1990-05-15 | 1998-03-31 | Alkermes Controlled Therapeutics Inc. Ii | Controlled release of antiparasitic agents in animals |
US6326198B1 (en) | 1990-06-14 | 2001-12-04 | Regents Of The University Of Michigan | Methods and compositions for the ex vivo replication of stem cells, for the optimization of hematopoietic progenitor cell cultures, and for increasing the metabolism, GM-CSF secretion and/or IL-6 secretion of human stromal cells |
US6010696A (en) * | 1990-11-16 | 2000-01-04 | Osiris Therapeutics, Inc. | Enhancing hematopoietic progenitor cell engraftment using mesenchymal stem cells |
US5486359A (en) * | 1990-11-16 | 1996-01-23 | Osiris Therapeutics, Inc. | Human mesenchymal stem cells |
US5733542A (en) * | 1990-11-16 | 1998-03-31 | Haynesworth; Stephen E. | Enhancing bone marrow engraftment using MSCS |
US5197985A (en) * | 1990-11-16 | 1993-03-30 | Caplan Arnold I | Method for enhancing the implantation and differentiation of marrow-derived mesenchymal cells |
US5837539A (en) | 1990-11-16 | 1998-11-17 | Osiris Therapeutics, Inc. | Monoclonal antibodies for human mesenchymal stem cells |
US5226914A (en) | 1990-11-16 | 1993-07-13 | Caplan Arnold I | Method for treating connective tissue disorders |
US5811094A (en) | 1990-11-16 | 1998-09-22 | Osiris Therapeutics, Inc. | Connective tissue regeneration using human mesenchymal stem cell preparations |
WO1992014455A1 (en) * | 1991-02-14 | 1992-09-03 | The Rockefeller University | METHOD FOR CONTROLLING ABNORMAL CONCENTRATION TNF α IN HUMAN TISSUES |
US5192312A (en) * | 1991-03-05 | 1993-03-09 | Colorado State University Research Foundation | Treated tissue for implantation and methods of treatment and use |
US5190556A (en) | 1991-03-19 | 1993-03-02 | O.B. Tech, Inc. | Cord cutter sampler |
US5744361A (en) | 1991-04-09 | 1998-04-28 | Indiana University | Expansion of human hematopoietic progenitor cells in a liquid medium |
WO1993004169A1 (en) | 1991-08-20 | 1993-03-04 | Genpharm International, Inc. | Gene targeting in animal cells using isogenic dna constructs |
US6057123A (en) | 1991-12-23 | 2000-05-02 | British Biotech Pharmaceuticals Limited | Stem cell inhibiting proteins |
US5668104A (en) | 1992-03-31 | 1997-09-16 | Toray Industries, Inc. | Hematopoietic stem cell growth-promoting compositions containing a fibroblast-derived fragment of fibronectin and a growth factor, and methods employing them in vitro or in vivo |
US5460964A (en) | 1992-04-03 | 1995-10-24 | Regents Of The University Of Minnesota | Method for culturing hematopoietic cells |
AU4543193A (en) | 1992-06-22 | 1994-01-24 | Henry E. Young | Scar inhibitory factor and use thereof |
US5672346A (en) | 1992-07-27 | 1997-09-30 | Indiana University Foundation | Human stem cell compositions and methods |
US5849553A (en) | 1992-07-27 | 1998-12-15 | California Institute Of Technology | Mammalian multipotent neural stem cells |
US5693482A (en) | 1992-07-27 | 1997-12-02 | California Institute Of Technology | Neural chest stem cell assay |
EP0669974A1 (en) | 1992-11-16 | 1995-09-06 | Rhone-Poulenc Rorer Pharmaceuticals Inc. | Pluripotential quiescent stem cell population |
US5772992A (en) | 1992-11-24 | 1998-06-30 | G.D. Searle & Co. | Compositions for co-administration of interleukin-3 mutants and other cytokines and hematopoietic factors |
US5591767A (en) * | 1993-01-25 | 1997-01-07 | Pharmetrix Corporation | Liquid reservoir transdermal patch for the administration of ketorolac |
US5654186A (en) | 1993-02-26 | 1997-08-05 | The Picower Institute For Medical Research | Blood-borne mesenchymal cells |
JPH08510997A (en) * | 1993-03-31 | 1996-11-19 | プロ−ニューロン,インコーポレイテッド | Stem cell growth inhibitors and uses thereof |
GB9308271D0 (en) | 1993-04-21 | 1993-06-02 | Univ Edinburgh | Method of isolating and/or enriching and/or selectively propagating pluripotential animal cells and animals for use in said method |
US5709854A (en) * | 1993-04-30 | 1998-01-20 | Massachusetts Institute Of Technology | Tissue formation by injecting a cell-polymeric solution that gels in vivo |
US5605914A (en) * | 1993-07-02 | 1997-02-25 | Celgene Corporation | Imides |
US5698579A (en) * | 1993-07-02 | 1997-12-16 | Celgene Corporation | Cyclic amides |
US5372581A (en) | 1993-07-21 | 1994-12-13 | Minneapolis Children's Services Corporation | Method and apparatus for placental blood collection |
IL107483A0 (en) | 1993-11-03 | 1994-02-27 | Yeda Res & Dev | Bone marrow transplantation |
US5599705A (en) * | 1993-11-16 | 1997-02-04 | Cameron; Robert B. | In vitro method for producing differentiated universally compatible mature human blood cells |
US5591625A (en) * | 1993-11-24 | 1997-01-07 | Case Western Reserve University | Transduced mesenchymal stem cells |
US6288030B1 (en) * | 1993-12-22 | 2001-09-11 | Amgen Inc. | Stem cell factor formulations and methods |
US6001654A (en) | 1994-01-28 | 1999-12-14 | California Institute Of Technology | Methods for differentiating neural stem cells to neurons or smooth muscle cells using TGT-β super family growth factors |
US5942496A (en) | 1994-02-18 | 1999-08-24 | The Regent Of The University Of Michigan | Methods and compositions for multiple gene transfer into bone cells |
DE69531638T2 (en) * | 1994-06-06 | 2004-06-17 | Osiris Therapeutics, Inc. | BIOMATRIX FOR TISSUE REGENATION |
US6174333B1 (en) * | 1994-06-06 | 2001-01-16 | Osiris Therapeutics, Inc. | Biomatrix for soft tissue regeneration using mesenchymal stem cells |
DE4422667A1 (en) | 1994-06-30 | 1996-01-04 | Boehringer Ingelheim Int | Process for the production and cultivation of hematopoietic progenitor cells |
US6103522A (en) * | 1994-07-20 | 2000-08-15 | Fred Hutchinson Cancer Research Center | Human marrow stromal cell lines which sustain hematopoiesis |
US5516532A (en) | 1994-08-05 | 1996-05-14 | Children's Medical Center Corporation | Injectable non-immunogenic cartilage and bone preparation |
US5827742A (en) | 1994-09-01 | 1998-10-27 | Beth Israel Deaconess Medical Center, Inc. | Method of selecting pluripotent hematopioetic progenitor cells |
US5665557A (en) | 1994-11-14 | 1997-09-09 | Systemix, Inc. | Method of purifying a population of cells enriched for hematopoietic stem cells populations of cells obtained thereby and methods of use thereof |
MX9701512A (en) * | 1994-11-16 | 1997-05-31 | Amgen Inc | Use of stem cell factor and soluble interleukin-6 receptor for the ex vivo expansion of hematopoietic multipotential cells. |
US5874301A (en) | 1994-11-21 | 1999-02-23 | National Jewish Center For Immunology And Respiratory Medicine | Embryonic cell populations and methods to isolate such populations |
US5914268A (en) | 1994-11-21 | 1999-06-22 | National Jewish Center For Immunology & Respiratory Medicine | Embryonic cell populations and methods to isolate such populations |
US5789147A (en) | 1994-12-05 | 1998-08-04 | New York Blood Center, Inc. | Method for concentrating white cells from whole blood by adding a red cell sedimentation reagent to whole anticoagulated blood |
US5736396A (en) | 1995-01-24 | 1998-04-07 | Case Western Reserve University | Lineage-directed induction of human mesenchymal stem cell differentiation |
US5695998A (en) * | 1995-02-10 | 1997-12-09 | Purdue Research Foundation | Submucosa as a growth substrate for islet cells |
US6011000A (en) * | 1995-03-03 | 2000-01-04 | Perrine; Susan P. | Compositions for the treatment of blood disorders |
US5906934A (en) | 1995-03-14 | 1999-05-25 | Morphogen Pharmaceuticals, Inc. | Mesenchymal stem cells for cartilage repair |
US5716616A (en) * | 1995-03-28 | 1998-02-10 | Thomas Jefferson University | Isolated stromal cells for treating diseases, disorders or conditions characterized by bone defects |
US5677139A (en) | 1995-04-21 | 1997-10-14 | President And Fellows Of Harvard College | In vitro differentiation of CD34+ progenitor cells into T lymphocytes |
US5733541A (en) * | 1995-04-21 | 1998-03-31 | The Regent Of The University Of Michigan | Hematopoietic cells: compositions and methods |
US5925567A (en) * | 1995-05-19 | 1999-07-20 | T. Breeders, Inc. | Selective expansion of target cell populations |
US5908782A (en) | 1995-06-05 | 1999-06-01 | Osiris Therapeutics, Inc. | Chemically defined medium for human mesenchymal stem cells |
US5830708A (en) | 1995-06-06 | 1998-11-03 | Advanced Tissue Sciences, Inc. | Methods for production of a naturally secreted extracellular matrix |
WO1996040875A1 (en) | 1995-06-07 | 1996-12-19 | Novartis Ag | Methods for obtaining compositions enriched for hematopoietic stem cells and antibodies for use therein |
US5654381A (en) | 1995-06-16 | 1997-08-05 | Massachusetts Institute Of Technology | Functionalized polyester graft copolymers |
US5877299A (en) * | 1995-06-16 | 1999-03-02 | Stemcell Technologies Inc. | Methods for preparing enriched human hematopoietic cell preparations |
US6306575B1 (en) | 1995-06-16 | 2001-10-23 | Stemcell Technologies, Inc. | Methods for preparing enriched human hematopoietic cell preparations |
US5858782A (en) * | 1995-11-13 | 1999-01-12 | Regents Of The University Of Michigan | Functional human hematopoietic cells |
US5922597A (en) | 1995-11-14 | 1999-07-13 | Regents Of The University Of Minnesota | Ex vivo culture of stem cells |
PT868505E (en) | 1995-11-16 | 2005-06-30 | Univ Case Western Reserve | IN VITRO CONDROGENIC INDUCTION OF HUMAN MESENCHINEAL STAMINA CELLS |
US6337387B1 (en) * | 1995-11-17 | 2002-01-08 | Asahi Kasei Kabushiki Kaisha | Differentiation-suppressive polypeptide |
US5716794A (en) * | 1996-03-29 | 1998-02-10 | Xybernaut Corporation | Celiac antigen |
US5919176A (en) * | 1996-05-14 | 1999-07-06 | Children's Hospital Medical Center Of Northern California | Apparatus and method for collecting blood from an umbilical cord |
US6281230B1 (en) * | 1996-07-24 | 2001-08-28 | Celgene Corporation | Isoindolines, method of use, and pharmaceutical compositions |
US5827740A (en) | 1996-07-30 | 1998-10-27 | Osiris Therapeutics, Inc. | Adipogenic differentiation of human mesenchymal stem cells |
US6358737B1 (en) * | 1996-07-31 | 2002-03-19 | Board Of Regents, The University Of Texas System | Osteocyte cell lines |
US5851984A (en) | 1996-08-16 | 1998-12-22 | Genentech, Inc. | Method of enhancing proliferation or differentiation of hematopoietic stem cells using Wnt polypeptides |
US5916202A (en) * | 1996-08-30 | 1999-06-29 | Haswell; John N. | Umbilical cord blood collection |
US6227202B1 (en) | 1996-09-03 | 2001-05-08 | Maulana Azad Medical College | Method of organogenesis and tissue regeneration/repair using surgical techniques |
US5945337A (en) | 1996-10-18 | 1999-08-31 | Quality Biological, Inc. | Method for culturing CD34+ cells in a serum-free medium |
US5969105A (en) | 1996-10-25 | 1999-10-19 | Feng; Yiqing | Stem cell factor receptor agonists |
US6335195B1 (en) * | 1997-01-28 | 2002-01-01 | Maret Corporation | Method for promoting hematopoietic and mesenchymal cell proliferation and differentiation |
JPH10295369A (en) * | 1997-02-26 | 1998-11-10 | Japan Tobacco Inc | Production of hematopoietic stem cell |
US6152142A (en) | 1997-02-28 | 2000-11-28 | Tseng; Scheffer C. G. | Grafts made from amniotic membrane; methods of separating, preserving, and using such grafts in surgeries |
US6231880B1 (en) | 1997-05-30 | 2001-05-15 | Susan P. Perrine | Compositions and administration of compositions for the treatment of blood disorders |
US6261549B1 (en) | 1997-07-03 | 2001-07-17 | Osiris Therapeutics, Inc. | Human mesenchymal stem cells from peripheral blood |
US6077708A (en) | 1997-07-18 | 2000-06-20 | Collins; Paul C. | Method of determining progenitor cell content of a hematopoietic cell culture |
US5879318A (en) * | 1997-08-18 | 1999-03-09 | Npbi International B.V. | Method of and closed system for collecting and processing umbilical cord blood |
WO1999011287A1 (en) * | 1997-09-04 | 1999-03-11 | Osiris Therapeutics, Inc. | Ligands that modulate differentiation of mesenchymal stem cells |
US5968829A (en) | 1997-09-05 | 1999-10-19 | Cytotherapeutics, Inc. | Human CNS neural stem cells |
US6093531A (en) | 1997-09-29 | 2000-07-25 | Neurospheres Holdings Ltd. | Generation of hematopoietic cells from multipotent neural stem cells |
US5874448A (en) * | 1997-11-18 | 1999-02-23 | Celgene Corporation | Substituted 2-(2,6 dioxo-3-fluoropiperidin-3-yl)-isoindolines and method of reducing TNFα levels |
US6248587B1 (en) | 1997-11-26 | 2001-06-19 | University Of Southern Cailfornia | Method for promoting mesenchymal stem and lineage-specific cell proliferation |
WO1999030723A1 (en) * | 1997-12-04 | 1999-06-24 | University Of Medicine And Dentistry Of New Jersey | Use of human umbilical cord blood for adoptive therapy |
US6059968A (en) | 1998-01-20 | 2000-05-09 | Baxter International Inc. | Systems for processing and storing placenta/umbilical cord blood |
CA2323073C (en) * | 1998-03-13 | 2010-06-22 | Osiris Therapeutics, Inc. | Uses for human non-autologous mesenchymal stem cells |
JP2002513762A (en) | 1998-05-04 | 2002-05-14 | ポイント セラピューティクス, インコーポレイテッド | Hematopoietic stimulation |
JP2002513545A (en) * | 1998-05-07 | 2002-05-14 | ザ ユニヴァーシティー オブ サウス フロリダ | Bone marrow cells as a source of neurons for brain and spinal cord repair |
US6255112B1 (en) | 1998-06-08 | 2001-07-03 | Osiris Therapeutics, Inc. | Regulation of hematopoietic stem cell differentiation by the use of human mesenchymal stem cells |
AU4336599A (en) * | 1998-06-08 | 1999-12-30 | Osiris Therapeutics, Inc. | (in vitro) maintenance of hematopoietic stem cells |
US6713245B2 (en) * | 1998-07-06 | 2004-03-30 | Diacrin, Inc. | Methods for storing neural cells such that they are suitable for transplantation |
US5958767A (en) | 1998-08-14 | 1999-09-28 | The Children's Medical Center Corp. | Engraftable human neural stem cells |
JP3517359B2 (en) | 1998-09-14 | 2004-04-12 | テルモ株式会社 | Cell separation / collection apparatus and cell separation / collection method |
WO2000017325A1 (en) | 1998-09-23 | 2000-03-30 | Mount Sinai Hospital | Trophoblast cell preparations |
AU1720400A (en) | 1998-11-12 | 2000-05-29 | Cell Science Therapeutics, Inc. | Lymphoid tissue-specific cell production from hematopoietic progenitor cells in three-dimensional devices |
US6548299B1 (en) | 1999-11-12 | 2003-04-15 | Mark J. Pykett | Lymphoid tissue-specific cell production from hematopoietic progenitor cells in three-dimensional devices |
US6184035B1 (en) * | 1998-11-18 | 2001-02-06 | California Institute Of Technology | Methods for isolation and activation of, and control of differentiation from, skeletal muscle stem or progenitor cells |
US6102871A (en) | 1998-11-23 | 2000-08-15 | Coe; Rosemarie O. | Blood collection funnel |
US6328765B1 (en) | 1998-12-03 | 2001-12-11 | Gore Enterprise Holdings, Inc. | Methods and articles for regenerating living tissue |
US20030007954A1 (en) * | 1999-04-12 | 2003-01-09 | Gail K. Naughton | Methods for using a three-dimensional stromal tissue to promote angiogenesis |
IN191359B (en) | 1999-04-20 | 2003-11-29 | Nat Inst Immunology | |
AU4860900A (en) | 1999-06-02 | 2000-12-18 | Lifebank Services, L.L.C. | Methods of isolation, cryopreservation, and therapeutic use of human amniotic epithelial cells |
US6333029B1 (en) * | 1999-06-30 | 2001-12-25 | Ethicon, Inc. | Porous tissue scaffoldings for the repair of regeneration of tissue |
US7015037B1 (en) * | 1999-08-05 | 2006-03-21 | Regents Of The University Of Minnesota | Multiponent adult stem cells and methods for isolation |
US8075881B2 (en) * | 1999-08-05 | 2011-12-13 | Regents Of The University Of Minnesota | Use of multipotent adult stem cells in treatment of myocardial infarction and congestive heart failure |
US6685936B2 (en) * | 1999-10-12 | 2004-02-03 | Osiris Therapeutics, Inc. | Suppressor cells induced by culture with mesenchymal stem cells for treatment of immune responses in transplantation |
US6280718B1 (en) | 1999-11-08 | 2001-08-28 | Wisconsin Alumni Reasearch Foundation | Hematopoietic differentiation of human pluripotent embryonic stem cells |
WO2001066698A1 (en) * | 2000-03-09 | 2001-09-13 | Cryo-Cell International, Inc. | Human cord blood as a source of neural tissue for repair of the brain and spinal cord |
WO2001075094A1 (en) | 2000-04-04 | 2001-10-11 | Thomas Jefferson University | Application of myeloid-origin cells to the nervous system |
US7282366B2 (en) * | 2000-04-27 | 2007-10-16 | Geron Corporation | Hepatocytes for therapy and drug screening made from embryonic stem cells |
EP1289557B1 (en) | 2000-06-06 | 2006-07-12 | Glaxo Group Limited | Cancer treatment composition containing an anti-neoplastic agent and a pde4 inhibitor |
US20050009876A1 (en) * | 2000-07-31 | 2005-01-13 | Bhagwat Shripad S. | Indazole compounds, compositions thereof and methods of treatment therewith |
US6538023B1 (en) * | 2000-09-15 | 2003-03-25 | Tsuyoshi Ohnishi | Therapeutic uses of green tea polyphenols for sickle cell disease |
US7560280B2 (en) | 2000-11-03 | 2009-07-14 | Kourion Therapeutics Gmbh | Human cord blood derived unrestricted somatic stem cells (USSC) |
WO2002044343A2 (en) | 2000-11-22 | 2002-06-06 | Geron Corporation | Tolerizing allografts of pluripotent stem cells |
US20080152629A1 (en) | 2000-12-06 | 2008-06-26 | James Edinger | Placental stem cell populations |
KR100915482B1 (en) | 2000-12-06 | 2009-09-03 | 하리리 로버트 제이 | Method of collecting placental stem cells |
US7311905B2 (en) | 2002-02-13 | 2007-12-25 | Anthrogenesis Corporation | Embryonic-like stem cells derived from post-partum mammalian placenta, and uses and methods of treatment using said cells |
US20030045552A1 (en) * | 2000-12-27 | 2003-03-06 | Robarge Michael J. | Isoindole-imide compounds, compositions, and uses thereof |
NZ528035A (en) | 2001-02-14 | 2005-07-29 | Robert J Hariri | Renovation and repopulation of decellularized tissues and cadaveric organs by stem cells |
EP1362095B1 (en) * | 2001-02-14 | 2015-05-27 | Anthrogenesis Corporation | Post-partum mammalian placenta, its use and placental stem cells therefrom |
US6987184B2 (en) * | 2001-02-15 | 2006-01-17 | Signal Pharmaceuticals, Llc | Isothiazoloanthrones, isoxazoloanthrones, isoindolanthrones and derivatives thereof as JNK inhibitors and compositions and methods related |
US20020132343A1 (en) * | 2001-03-19 | 2002-09-19 | Clark Lum | System and method for delivering umbilical cord-derived tissue-matched stem cells for transplantation |
US20030044977A1 (en) * | 2001-08-10 | 2003-03-06 | Norio Sakuragawa | Human stem cells originated from human amniotic mesenchymal cell layer |
WO2003018780A1 (en) * | 2001-08-27 | 2003-03-06 | Advanced Cell Technology, Inc. | De-differentiation and re-differentiation of somatic cells and production of cells for cell therapies |
US9969980B2 (en) * | 2001-09-21 | 2018-05-15 | Garnet Biotherapeutics | Cell populations which co-express CD49c and CD90 |
JP2005508393A (en) | 2001-11-09 | 2005-03-31 | アーテセル・サイエンシズ・インコーポレーテツド | Methods and compositions for the use of stromal cells to support embryonic and adult stem cells |
DE60233248D1 (en) | 2001-11-15 | 2009-09-17 | Childrens Medical Center | PROCESS FOR THE ISOLATION, EXPANSION AND DIFFERENTIATION OF FEDERAL STRAIN CELLS FROM CHORION ZOTTE, FRUIT WATER AND PLAZENTA AND THERAPEUTIC USES THEREOF |
US20030099621A1 (en) | 2001-11-29 | 2003-05-29 | Robert Chow | Stem cell screening and transplantation therapy for HIV infection |
US7799324B2 (en) | 2001-12-07 | 2010-09-21 | Geron Corporation | Using undifferentiated embryonic stem cells to control the immune system |
ATE464373T1 (en) * | 2001-12-21 | 2010-04-15 | Mount Sinai Hospital Corp | CELLULAR COMPOSITIONS AND METHODS FOR THE PREPARATION AND USE THEREOF |
WO2003061591A2 (en) * | 2002-01-22 | 2003-07-31 | Advanced Cell Technology, Inc. | Stem cell-derived endothelial cells modified to disrupt tumor angiogenesis |
US7736892B2 (en) | 2002-02-25 | 2010-06-15 | Kansas State University Research Foundation | Cultures, products and methods using umbilical cord matrix cells |
WO2003077865A2 (en) | 2002-03-15 | 2003-09-25 | Baxter International Inc. | Methods and compositions for directing cells to target organs |
US20030187515A1 (en) * | 2002-03-26 | 2003-10-02 | Hariri Robert J. | Collagen biofabric and methods of preparing and using the collagen biofabric |
US7498171B2 (en) | 2002-04-12 | 2009-03-03 | Anthrogenesis Corporation | Modulation of stem and progenitor cell differentiation, assays, and uses thereof |
KR20050000398A (en) | 2002-04-12 | 2005-01-03 | 셀진 코포레이션 | Methods for identification of modulators of angiogenesis, compounds discovered thereby, and methods of treatment using the compounds |
CA2481385A1 (en) | 2002-04-12 | 2003-10-23 | Celgene Corporation | Modulation of stem and progenitor cell differentiation, assays, and uses thereof |
US20040161419A1 (en) | 2002-04-19 | 2004-08-19 | Strom Stephen C. | Placental stem cells and uses thereof |
CA2483010A1 (en) * | 2002-04-19 | 2003-10-30 | University Of Pittsburgh Of The Commonwealth System Of Higher Education | Placental derived stem cells and uses thereof |
US20050058641A1 (en) * | 2002-05-22 | 2005-03-17 | Siemionow Maria Z. | Tolerance induction and maintenance in hematopoietic stem cell allografts |
EP1525308A4 (en) * | 2002-05-30 | 2006-11-02 | Celgene Corp | Methods of using jnk or mkk inhibitors to modulate cell differentiation and to treat myeloproliferative disorders and myelodysplastic syndromes |
JP3988559B2 (en) * | 2002-07-18 | 2007-10-10 | オムロン株式会社 | COMMUNICATION SYSTEM, COMMUNICATION DEVICE, AND COMMUNICATION CONTROL METHOD |
US7422736B2 (en) * | 2002-07-26 | 2008-09-09 | Food Industry Research And Development Institute | Somatic pluripotent cells |
US9969977B2 (en) * | 2002-09-20 | 2018-05-15 | Garnet Biotherapeutics | Cell populations which co-express CD49c and CD90 |
EP1571910A4 (en) | 2002-11-26 | 2009-10-28 | Anthrogenesis Corp | Cytotherapeutics, cytotherapeutic units and methods for treatments using them |
NZ542127A (en) | 2003-02-13 | 2008-04-30 | Anthrogenesis Corp | Use of umbilical cord blood to treat individuals having a disease, disorder or condition |
WO2005038012A2 (en) * | 2003-06-27 | 2005-04-28 | Ethicon Incorporated | Cartilage and bone repair and regeneration using postpartum-derived cells |
US7569385B2 (en) * | 2003-08-14 | 2009-08-04 | The Regents Of The University Of California | Multipotent amniotic fetal stem cells |
US20050089513A1 (en) | 2003-10-28 | 2005-04-28 | Norio Sakuragawa | Side population cells originated from human amnion and their uses |
WO2005047491A2 (en) | 2003-11-10 | 2005-05-26 | Amgen Inc. | Methods of using g-csf mobilized c-kit+cells in the production of embryoid body-like cell clusters for tissue repair and in the treatment of cardiac myopathy |
WO2005051942A1 (en) * | 2003-11-19 | 2005-06-09 | Signal Pharmaceuticals, Llc | Indazole compounds and methods of use thereof as protein kinase inhibitors |
TWI338714B (en) | 2003-12-02 | 2011-03-11 | Cathay General Hospital | Method of isolation and enrichment of mesenchymal stem cells from amniotic fluid |
KR20110116225A (en) | 2003-12-02 | 2011-10-25 | 셀진 코포레이션 | Methods and compositions for the treatment and management of hemoglobinopathy and anemia |
US20050176139A1 (en) | 2004-01-12 | 2005-08-11 | Yao-Chang Chen | Placental stem cell and methods thereof |
US20050266391A1 (en) | 2004-01-15 | 2005-12-01 | Bennett Brydon L | Methods for preserving tissue |
NZ550027A (en) | 2004-03-26 | 2009-03-31 | Celgene Corp | Systems and methods for providing a stem cell bank |
US7244759B2 (en) | 2004-07-28 | 2007-07-17 | Celgene Corporation | Isoindoline compounds and methods of making and using the same |
US7147626B2 (en) | 2004-09-23 | 2006-12-12 | Celgene Corporation | Cord blood and placenta collection kit |
US7909806B2 (en) | 2004-09-23 | 2011-03-22 | Anthrogenesis Corporation | Cord blood and placenta collection kit |
US9056093B2 (en) * | 2005-01-07 | 2015-06-16 | Wake Forest University Health Sciences | Regeneration of pancreatic islets by amniotic fluid stem cell therapy |
WO2006091766A2 (en) * | 2005-02-24 | 2006-08-31 | Jau-Nan Lee | Human trophoblast stem cells and use thereof |
ZA200800144B (en) | 2005-06-10 | 2010-02-24 | Celgene Corp | Human placental collagen compositions, processes for their preparation, methods of their use and kits comprising the compositions |
KR20080026198A (en) | 2005-06-30 | 2008-03-24 | 안트로제네시스 코포레이션 | Repair of tympanic membrane using placenta derived collagen biofabric |
WO2007009062A2 (en) | 2005-07-13 | 2007-01-18 | Anthrogenesis Corporation | Treatment of leg ulcers using placenta derived collagen biofabric |
WO2007009061A2 (en) | 2005-07-13 | 2007-01-18 | Anthrogenesis Corporation | Ocular plug formed from placenta derived collagen biofabric |
WO2007011693A2 (en) * | 2005-07-14 | 2007-01-25 | Medistem Laboratories, Inc. | Compositions of placentally-derived stem cells for the treatment of cancer |
ES2452595T3 (en) | 2005-10-13 | 2014-04-02 | Anthrogenesis Corporation | Immunomodulation using placental stem cells |
EP2368973A1 (en) | 2005-10-13 | 2011-09-28 | Anthrogenesis Corporation | Production Of Oligodendrocytes From Placenta-Derived Stem Cells |
US8455250B2 (en) | 2005-12-29 | 2013-06-04 | Anthrogenesis Corporation | Co-culture of placental stem cells and stem cells from a second source |
PL2471904T3 (en) | 2005-12-29 | 2019-08-30 | Celularity, Inc. | Placental stem cell populations |
EP1974013A2 (en) | 2005-12-29 | 2008-10-01 | Anthrogenesis Corporation | Improved composition for collecting and preserving placental stem cells and methods of using the composition |
ZA200810412B (en) | 2006-06-09 | 2010-03-31 | Anthrogenesis Corp | Placental niche and use thereof to culture stem cells |
US7993918B2 (en) | 2006-08-04 | 2011-08-09 | Anthrogenesis Corporation | Tumor suppression using placental stem cells |
WO2008021391A1 (en) * | 2006-08-15 | 2008-02-21 | Anthrogenesis Corporation | Umbilical cord biomaterial for medical use |
WO2008042441A1 (en) | 2006-10-03 | 2008-04-10 | Anthrogenesis Corporation | Use of umbilical cord biomaterial for ocular surgery |
WO2008060377A2 (en) | 2006-10-04 | 2008-05-22 | Anthrogenesis Corporation | Placental or umbilical cord tissue compositions |
CA3178363A1 (en) | 2006-10-06 | 2008-05-15 | Celularity Inc. | Human placental collagen compositions, and methods of making and using the same |
CA2850793A1 (en) | 2006-10-23 | 2008-05-02 | Anthrogenesis Corporation | Methods and compositions for treatment of bone defects with placental cell populations |
EP2129775A1 (en) | 2007-02-12 | 2009-12-09 | Anthrogenesis Corporation | Hepatocytes and chondrocytes from adherent placental stem cells; and cd34+, cd45- placental stem cell-enriched cell populations |
AU2008216749B2 (en) | 2007-02-12 | 2014-03-13 | Celularity Inc. | Treatment of inflammatory diseases using placental stem cells |
KR20220122774A (en) | 2007-09-26 | 2022-09-02 | 셀룰래리티 인코포레이티드 | Angiogenic cells from human placental perfusate |
EP2783692B1 (en) | 2007-09-28 | 2019-01-02 | Celularity, Inc. | Tumor suppression using human placental perfusate and human placenta-derived intermediate natural killer cells |
MX2010005018A (en) | 2007-11-07 | 2010-05-27 | Anthrogenesis Corp | Treatment of premature birth complications. |
MX2011001990A (en) | 2008-08-20 | 2011-03-29 | Anthrogenesis Corp | Improved cell composition and methods of making the same. |
CN105796602A (en) | 2008-08-20 | 2016-07-27 | 人类起源公司 | Treatment of stroke using isolated placental cells |
CN102176919A (en) | 2008-08-22 | 2011-09-07 | 人类起源公司 | Methods and compositions for treatment of bone defects with placental cell populations |
KR20110086176A (en) | 2008-11-19 | 2011-07-27 | 안트로제네시스 코포레이션 | Amnion derived adherent cells |
MX2011005230A (en) | 2008-11-21 | 2011-06-16 | Anthrogenesis Corp | Treatment of diseases, disorders or conditions of the lung using placental cells. |
CA2767014C (en) * | 2009-07-02 | 2022-01-25 | Anthrogenesis Corporation | Method of producing erythrocytes without feeder cells |
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JP2006509770A (en) | 2006-03-23 |
BR0316695A (en) | 2005-10-18 |
KR20100125479A (en) | 2010-11-30 |
WO2004047770A2 (en) | 2004-06-10 |
CN1717177A (en) | 2006-01-04 |
AU2003298775B2 (en) | 2008-07-17 |
AU2003298775A1 (en) | 2004-06-18 |
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