Drug – bio-affecting and body treating compositions – Whole live micro-organism – cell – or virus containing – Genetically modified micro-organism – cell – or virus
Reexamination Certificate
1999-11-04
2002-12-10
Wehbé, Anne Marie S. (Department: 1632)
Drug, bio-affecting and body treating compositions
Whole live micro-organism, cell, or virus containing
Genetically modified micro-organism, cell, or virus
C424S093200, C514S04400A, C435S320100, C435S325000, C536S023400
Reexamination Certificate
active
06491908
ABSTRACT:
FIELD OF THE INVENTION
The invention relates to methods and compositions for the elimination of T cells that recognize specific preselected targets. In particular, the invention provides methods and compositions for the treatment of graft rejection and autoimmune diseases. In one embodiment, the invention provides modified killer cells that bear a preselected target molecule (e.g. an MHC molecule) attached to a signal transduction molecule (e.g. the zeta (&zgr;) chain of the T cell receptor or the low-affinity receptor for IgG, Fc&ggr;RIII (CD16)). Recognition of the preselected molecule by a T cell activates the killer cell through the signal transduction molecule and the activated killer cell then kills or inhibits the T cell.
BACKGROUND OF THE INVENTION
Autoimmune diseases are pathological states mediated by an undesired immune response. More than 30 autoimmune diseases are presently known; these include many which have received much public attention, including myasthenia gravis (MG) and multiple sclerosis (MS). Characteristic of these diseases is the attack by the immune system on the tissues of the victim—these tissue antigens being non-immunogenic in non-diseased individuals because of the tolerance of the immune system to “self.” In autoimmune diseases, this tolerance apparently is compromised, and the tissue of the afflicted subject is treated as an invader—i.e., the immune system sets about destroying this presumed foreign target.
Similarly in graft rejection the recipient of a graft or organ transplant mounts an immune response against the foreign (non-self) tissue. In this case the response is not a loss of tolerance, but rather a legitimate, although undesired, response directed against a foreign tissue.
A crude approach to treating graft or organ rejection or autoimmune disease is, of course, general immunosuppression. This has the obvious disadvantage of crippling the ability of the subject to respond to infectious organisms or tumors. An only slightly more sophisticated approach relies on the removal of antibodies or immune complexes involving the target tissue. This also has adverse side effects, is difficult to accomplish, and is not particularly effective.
Various approaches have been attempted to interdict the immune response to specific antigens. For example, the autoantigen thyroglobulin has been conjugated to ricin A and the conjugate was shown to suppress specifically the in vitro antibody response of lymphocytes which normally respond to this antigen. It was suggested that such immunotoxins would specifically delete autoantibody-secreting lymphocyte clones (Rennie, et al.,
Lancet
(Dec. 10, 1983) 1338-1339).
Diener, et al.,
Science
231: 148-150 (1986) suggested the construction of compounds which cause antigen-specific suppression of lymphocyte function by conjugating daunomycin to the hapten (in this case, of ovalbumin) using an acid-sensitive spacer. The conjugate caused hapten-specific inhibition of antibody secretion by B lymphocytes in vitro and in vivo. A conjugate of daunomycin (with an acid-sensitive spacer) to a monoclonal antibody-specific to T cells also eliminated the response by T-lymphocytes to concanavalin A.
Steerz et al.,
J. Immunol
. 134: 841-846 (1985) utilized radiation as the toxic element in a toxin conjugate. Rats were administered a radioactively labeled, purified receptor from electric fish, prior to injection with cold receptor. Injection with this receptor is a standard procedure to induce experimental autoimmune myasthenia gravis (EAMG). Control rats that received preinjection only either of cold receptor or radiolabeled albumin, prior to administration of receptor to induce the disease develop the symptoms of EAMG; those pretreated with radioactively-labeled receptor showed reduced symptoms. It was surmised that the labeled, and therefore destructive, receptor selectively eliminated immunocompetent cells. Similar work utilizing a ricin/receptor conjugate for pretreatment was reported by Killen, et al.,
J. Immunol
. 133: 2549-2553 (1984).
A less specific approach which results in the destruction of T cells in general is treatment with an IL-2/toxin conjugate as reported by Hixson,
Medical Tribune
, (Jan. 28, 1988) 4-5. In a converse, but related, approach Liu et al.,
Science
239: 395-397 (1988), report a method to “link up” cytotoxic T cells with a desired target, regardless of the cytotoxic T cell specificity. In this approach, antibody specific to the universal cytotoxic T-lymphocytes to destroy human melanoma cells when melanocyte-stimulating hormone was the hormone used.
Recent experiments have shown that, under certain circumstances, anergy or nonresponsiveness can be induced in autoreactive lymphocytes (see, Schwartz,
Cell
1073-1081 (1989)). In vitro experiments suggest that antigen presentation by MHC Class II molecules in the absence of co-stimulatory signals induces a state of proliferative non-responsiveness in syngeneic T cells (Quill et al.,
J. Immunol
. 138: 3704-3712 (1987)). These reports, however, provide no clear evidence that induction of anergy in vivo is possible or that autoimmune disease or graft rejection can be effectively treated in this manner.
SUMMARY OF THE INVENTION
This invention provides for a method of selectively inhibiting or killing T cells that recognize a specific preselected target molecule. The invention provides modified killer cells that bear a signal transduction molecule (e.g. the zeta (&zgr;) chain of a T cell receptor) to which is attached the preselected target molecule (e.g. the extracellular domain of a particular MHC molecule). Recognition of the preselected molecule by a T cell activates the killer cell which then kills or inhibits the T cell. Where the preselected molecule is an extracellular domain of an MHC from a xenograft or an allograft, treatment of the graft recipient with the modified killer T cells delays or inhibits graft rejection. Similarly where the preselected molecule is an MHC that binds the antigenic determinant of the autoimmune disease, treatment of the organism with the modified killer T cells mitigates the autoimmune response directed against that antigenic determinant.
This invention provides both for methods and for compositions for the selective inhibition or destruction of T cells that specifically recognize a preselected target molecule. Thus, in one embodiment, this invention provides a method of inhibiting a T cell that specifically recognizes a preselected target molecule. The method involves contacting the T cell with a killer cell comprising a signal transduction molecule attached to a preselected target molecule that is recognized by the T cell. Suitable killer cells include, but are not limited to CTLs, NK cells, macrophages, or the precursors of these cells (e.g. hematopoietic stem cells). The signal transduction molecule may be chemically conjugated to the target molecule, or the transduction molecule/target molecule chimera may be recombinantly expressed as a fusion protein. Preferred signal transduction molecules include the &zgr; chain of a T cell receptor, the &ggr; chain of an FC receptor, the &eegr; chain, the &egr; chain, and the &dgr; chain, rFC&egr;R1&bgr;, EBV-LMP2A, BLV gp30, TAMs and ARAMs, with the &zgr; chain being most preferred.
The killer cell may be an cell that is cytotoxic to other cells when it is activated. Preferred killer cells include cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells.
Preferred target molecules include the extracellular domains of an MHC molecule, more preferably a human MHC molecule (HLA), or the extracellular domains of an MHC molecule (e.g. HLA) complexed with an antigenic determinant of an autoimmune disease (e.g. human type II collagen, or myelin basic protein NBP) or with other peptides.
In a particularly preferred method, the preselected target molecule is the extracellular domain of an MHC molecule of an allograft or a xenograft transplanted to a recipient and the killer cell is administered to the recipient where it inhibits T cells that recognize the MHC molecule and
S. Wehbé Anne Marie
The United States of America as represented by the Secretary of
Townsend and Townsend / and Crew LLP
LandOfFree
Selective elimination of T cells that recognize specific... does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Selective elimination of T cells that recognize specific..., we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Selective elimination of T cells that recognize specific... will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-2980774