Devices for cloaking transplanted cells

Details Devices for cloaking transplanted cells Devices for cloaking transplanted cells

1997-12-24

2002-04-09

Jones, Dwayne C. (Department: 1614)

Drug, bio-affecting and body treating compositions

Preparations characterized by special physical form

Implant or insert

C424S423000, C424S424000, C424S426000, C604S891100, C514S866000

Reexamination Certificate

active

06368612

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.
SUMMARY OF THE INVENTION
A variety of devices can be used to contain or cloak 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. Semipermiable components are used to inhibit the ability of host molecules to enter the device and attack the source of therapeutic substance. The inventors have discovered that release, by the device, of components of the source of therapeutic substance, can stimulate a host response against the device and that capture of such components, prior to release or prior to becoming available to the immune system of the host, 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 capture agent, e.g., an antibody directed against an antigen of the source of a therapeutic substance, which sequesters therapeutic source molecules, 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 capture agent, e.g., an antibody which binds a component of the therapeutic substance, disposed within or on a semipermeable component. The capture agents are preferably immobilized within the interior of the device or on its surface or are in a different compartment than the source of a therapeutic substance, or otherwise immobilized to keep it from contacting the source of a therapeutic substance. The capture agent can, e.g., coupled to a substrate, e.g., an inert bead in a compartment of the microreactor, or can be coupled to the surface of the microreactor, or to the surface of a component of the microreactor.
In preferred embodiments, the capture agent is an antibody or antibody fragment, even more preferably, the capture agent is an antibody or antibody fragment which binds an antigen or epitope other than the therapeutic substance released by the source. In an even more preferred embodiment, the antibody or antibody fragment is directed against an antigen which is an MHC class I, an MHC class II, an SLA class I, or an SLA class II antigen. In another preferred embodiment, the antibody or antibody fragment is a human antibody, a humanized antibody, an antibody which is engineered to minimize host response, or an engineered binding protein of a parental protein which is preferably of human origin.
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, or sheep, or a non-human primate species.
In preferred embodiments, the cell is a pancreatic islet cell. In preferred embodiments, the pancreatic islet is from a dog, pig, goat, rabbit goat, horse, cow, sheep, or a 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; the cell is a skin, astroglial, or myoblast cell.
In preferred embodiments, the source of a therapeutic substance (and preferably the capture 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., devices 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 separates the source of a therapeutic substance (and preferably the capture 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 capture 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 source of a therapeutic substance, e.g., a cell or tissue, is embedded. The gel can be a hydrogel. In preferred embodiments, the hydrogel includes agarose, agar, collagen, polyethylene glycol (PEG), polyethylene oxide (PEO), or alginate. The agarose or alginate can have a high number of guluronic acid or a high number of mannuronic acid monomers. The microcapsule or macrocapsule can include a sem

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