Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Animal or plant cell
Reexamination Certificate
1997-08-01
2001-09-11
Naff, David M. (Department: 1651)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Animal or plant cell
C424S130100, C424S423000, C435S177000, C435S178000, C435S182000, C435S382000, C435S395000, C435S397000, C436S528000, C436S529000, C436S535000, C530S812000, C530S813000, C530S817000
Reexamination Certificate
active
06287558
ABSTRACT:
The invention relates to inhibiting damage to donor tissue in a device in contact with a host tissue.
BACKGROUND OF THE INVENTION
Transplantation of donor tissue into a recipient can be used to treat a wide variety of disorders, including heart disease, neoplastic disease, and endocrine disease. The clinical application of transplantation-based therapies are, however, limited by several factors. These factors include immune rejection of transplanted allogeneic or xenogeneic tissue by the transplant recipient, a shortage of allogeneic donor-tissue, and donor-propagated immune attack of recipient tissue (graft-versus-host-disease).
Immune rejection of transplanted donor-tissue can be the most serious barrier to more widespread availability of the benefits of transplantation-based therapies. Implantation of allogeneic or xenogeneic donor-tissue into an immunocompetent recipient generally results in a vigorous and destructive immune response directed against the donor-graft. Efforts to prevent immune-based destruction of donor tissue have generally fallen into two categories. In one approach, efforts have been directed to moderating the recipient's immune response, e.g., by the induction of specific immunological tolerance to transplanted tissue, or much more frequently, by the administration of broad-spectrum immune suppressants, e.g., cyclosporin. In the other major approach, efforts to prolong the acceptance of a donor-graft have been directed to rendering the donor-graft less susceptible to attack, e.g., by immunoisolating the donor-tissue by encapsulating it in a way which minimizes contact of elements of the recipient's immune system with the encapsulated donor tissue.
Immunoisolation is particularly attractive for the treatment of endocrine disorders or in hormone or enzyme replacement therapies. For example, the implantation of immunoisolated pancreatic islet cells can be used to restore glucose-responsive insulin function in a diabetic recipient. Islets can be placed in a mechanical enclosure, or can be coated with a material, which allows relatively free diffusion of glucose, insulin, nutrients, and cellular waste products but which is impervious to components of the recipient's immune system.
Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although methods and materials similar or equivalent to those herein can be used in the practice or testing of the present invention, the preferred methods and materials are described below. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference. In addition, the materials, methods, and examples are illustrative only and not intended to be limiting.
SUMMARY OF THE INVENTION
A variety of devices can be used to contain a source of a therapeutic substance, often cells, which source provides the substance to a host or recipient subject. Such devices include implantable devices, of both the diffusion and perfusion types, and extra corporeal devices, e.g., those through which blood of the host or recipient is passed. In such devices, host molecules can attack the source of the therapeutic substance and impair the function of the device. The inventors have discovered that the inclusion in such a device of a rescue agent, e.g., an agent which sequesters an unwanted host cell molecule or which otherwise inhibits the activity of an unwanted host molecule, can improve the performance of the device, e.g., by extending its useful lifetime.
The inventors have discovered that the inclusion in an implantable device of a rescue agent, e.g., an agent which sequesters an unwanted host cell molecule or which otherwise inhibits the activity of an unwanted host molecule, can improve the performance of the device, e.g., by extending its useful lifetime.
Accordingly, the invention features, an implantable device which includes a source of a therapeutic substance, e.g., an islet, and a rescue agent, e.g., an antibody which binds host antibodies, disposed within a semipermeable component.
In preferred embodiments the implantable device includes a cell or tissue. The cell or tissue can be autologous, allogeneic, or xenogeneic, with regard to the subject. A xenogeneic cell or tissue can be from a species which is concordant or discordant with the subject. The cell or tissue can be from the subject, but if it is from the subject, it is preferably genetically engineered to express a substance not normally expressed by or on that cell or tissue.
In preferred embodiments the cell or tissue is from a dog, pig, goat, rabbit, horse, cow, sheep, or a non-human primate.
In preferred embodiments the cell is a pancreatic islet cell. In preferred embodiments, the pancreatic islet is from a dog, pig, goat, rabbit, horse, cow, sheep, or non-human primate. In particularly preferred embodiments, the pancreatic islet is from a pig. In preferred embodiments, the pancreatic islet is from a human other than the subject.
In preferred embodiments, the cell or tissue is genetically engineered.
The cell or tissue can be from the pancreas, adrenal gland, brain, kidney, liver, thymus, parathyroid or thyroid. In a preferred embodiment, the cell is a cultured cell. In a preferred embodiment, the cell is from a primary culture. In a preferred embodiment, the cell has been treated with a cytokine or a growth factor.
In preferred embodiments: the cell is an immortalized cell; the cell is a blood cell; the cell or tissue is a fetal cell or tissue; the cell is a skin, astroglial, or myoblast cell.
In preferred embodiments the source of a therapeutic substance (and preferably the rescue agent) is immunoisolated from the host, e.g., it is isolated from contact with one or more host immune components, e.g., antibodies or components of the complement system.
In preferred embodiments the implantable device is a perfusion device, e.g., a device through which the flow of blood is directed, e.g., intravascular devices, as e.g., in an arterial or venous shunt.
In preferred embodiments the device can be a microcapsule or a macrocapsular device, e.g., a hollow fiber, a membrane chamber, or other device which separate the source of a therapeutic substance (and preferably the rescue agent) from the host by an artificial semi-permeable barrier.
In preferred embodiments the device serves to physically contain the source of a therapeutic substance, e.g., donor cells or tissues (and preferably the rescue agent), keeping them in a contained location, at least temporarily separated from the implantation site or tissues of the host.
In preferred embodiments the device is a microcapsule or macrocapsule. It can include a gel member, e.g., a shape-retaining gel member, in which a cell or tissue is embedded. The gel can be a hydrogel. In preferred embodiments the hydrogel includes agarose, agar, collagen, polyethylene oxide (PEO), or alginate. The agarose or alginate can have a higher number of guluronic acid than mannuronic acid monomers. The microcapsule or macrocapsule can include a semipermeable membrane or coating, e.g., a semipermeable coating which surrounds a gel component, e.g. a gel core in which a cell or tissue is embedded. The semipermeable membrane can include a polymer, e.g., a positively charged polymer. By way of example, the positively charged polymer can be a polyamino acid. In preferred embodiments, the positively charged polymer includes lysine or ornithine. In a particularly preferred embodiment, the positively charged polymer is polylysine or another polymer of one or more positively charged amino acids. In preferred embodiments the coating can include chitosan.
In another aspect, the invention features, a composite microreactor which includes:
(a) one, or a plurality, of an internal particle which includes:
(i) a source of a therapeutic substance, e.g., an islet;
(ii) an internal particle matrix, e.g., a gel core or a solid particle, which contacts the source;
(iii) (optionally) an
Chick William
Ecker Dawn M.
Lanza Robert P.
Marsh Joanne P.
Ringeling John
BioHybrio Technologies LLC
Naff David M.
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